Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5- (Phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents

Article abstract of DOI:10.1016/j.ejmech.2011.08.048

We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were

Full text of DOI:10.1016/j.ejmech.2011.08.048

European Journal of Medicinal Chemistry 46 (2011) 5416e5434
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(Phenyl)
pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents
,
Pamela Kassisa, Joanna Brzeszcza e, Valérie Bénéteaua, Olivier Lozachc, Laurent Meijerc, Rémi Le Guéveld,
d
e
b
a
a,
*
ꢀ
Christiane Guillouzo , Krzysztof Lewinski , Stéphane Bourg , Lionel Colliandre , Sylvain Routier
,
,
Jean-Yves Méroura
*
a Institut de Chimie Organique et Analytique, Université d’Orléans, CNRS UMR 6005, B.P. 6759, 45067 Orléans Cedex 2, France
b Fédération de recherche Physique et Chimie du Vivant, Université d’Orléans, CNRS FR 2708, Rue Charles Sadron, 45071 Orléans Cedex 2, France
c C.N.R.S., Cell Cycle Group & UPS2682, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France
d Hôpital de Pontchaillou, INSERM U-522, 65033 Rennes Cedex, France
e Faculty of Chemistry, Jagiellonian University, ul. R. Ingardena 3, 30-060 Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine,
3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as
potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine
and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the
3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the
V-shaped family were in the micromolar range. Kinase assays were conducted and showed that
compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity
Received 20 June 2011
Received in revised form
29 August 2011
Accepted 31 August 2011
Available online 7 September 2011
Keywords:
Indole
Pyridine
Pyrazine
CDK
over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 mM).
Compound 11 was also found to be the most potent compound in the series and was identified as a new
lead for DYRK1A inhibitor discovery (IC50 ¼ 60 nM). Docking studies were carried out in order to
investigate the inhibition of DYRK1A.
GSK3
DYRK1A
Ó 2011 Elsevier Masson SAS. All rights reserved.
Cytotoxicity
Molecular modeling
1. Introduction
Alzheimer’s disease; the implication of GSK3 in cancer develop-
ment has been additionally proven [13,14]. Several drugs are able to
More than 500 protein kinases control the phosphorylation of
proteins in cellular life [1,2]. Alterations of this process are found in
numerous human pathologies, hence the interest in the search for
kinase inhibitors [3,4]. This interest was boosted following the
approval of the first marketed inhibitor GleevecÔ, used in myeloid
leukaemia [5]. Among all the kinases, cyclin-dependent kinases
(CDKs), which regulate the cell cycle and apoptosis, have been well
studied [6e10]. CDKs are also involved in neurodegenerative
disorders [11] such as Alzheimer’s disease. Other related kinases
such as glycogen synthase kinase GSK3 [12] induce neuro-
degeneration and deficits in memory formation related to
efficiently inhibit these enzymes and some of them are currently in
clinical assays, many of them containing an indole structure [15,16].
The indole scaffold is a popular privileged structure encoun-
tered in medicinal chemistry [17,18]. The discovery of plant indole
alkaloids or marine indolic drugs, which exhibit a wide range of
biological properties, greatly supports this privileged structure. The
design of new drugs is often based on core scaffolds with an indole
structure. In the indolocarbazole series, for example, our group
developed naphtho [19] and azaindolocarbazole [20] derivatives as
cytotoxic agents and/or check point kinase 1 inhibitors.
We have now started another program aimed at developing CDK
inhibitors on V-shaped structures. We recently developed the
synthesis of tris-aromatic compounds of the A-C type, i.e. a pyridine
(or a pyrimidine) core substituted respectively in positions C-3,5 or
C-2,5 by a phenyl or an indole motif [21e23]. These three AeC
structures were synthesized in order to partially mimic some
* Corresponding authors. Tel.: þ33 2 38 49 48 53; fax: þ33 2 38 41 72 81.
E-mail addresses: sylvain.routier@univ-orleans.fr (S. Routier), jean-yves.
merour@univ-orleans.fr (J.-Y. Mérour).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.08.048

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5417
A
X = CH, N
n = 2,3
R = (CH2)n-N(CH3)2
Botryllazine
Dragmacidin D
Hyrtinadine A
E
D
C
B
Fig. 1. Related synthetic or natural products and envisioned derivatives.
natural bis indole alkaloids such as Dragmacidin D [24], Hyrtina-
dine A [25], Botryllazine [26] or the synthetic bis indole derivatives
D [27] and E [28] (Fig. 1).
condensation with tributylstannyl chloride at ꢀ78 ꢁC (Scheme 1).
The resulting stannylated indole 3 was involved in a mono Stille
reaction with 3,5-dibromopyridine (1.0 eq.) in THF in presence of
CuI, Pd(PPh3)4 (5%) under microwave irradiation at 100 ꢁC for
20 min [23,30]. The bromopyridine 4 was obtained in a near
quantitative yield.
The promising preliminary biological evaluations (i.e. CDK
inhibition and cytotoxic properties) of our analogs prompted us to
mix structures of type A and B and investigate compounds of type C
with various substituents on the indole and phenyl rings with
a view to enhancing biological activity and in particular kinase
inhibition. The substituents would be chosen for their ability to
accept or donate H-bonds with the residues of the active ATP site of
kinases [23]. CDK, GSK and DYRK1A are privileged targets for their
implication in cancer or neurodegenerative diseases.
In this paper, we present the synthesis of a new library corre-
sponding to the general indole structure I (Fig. 2) from IIeIV by
using palladium catalyzed cross-coupling reactions (Stille, Suzuki
and Buchwald) mostly carried out under microwave irradiation.
The biological activity of the final compounds as kinase inhibitors
and cytotoxic agents are given and SAR are explored.
The second aromatic moiety was next introduced under
a
Suzuki-Miyaura type reaction using (4-methoxyphenyl, 4-
cyanophenyl or 4-methanesulfonylphenyl) boronic acids. The
reaction was carried out with a small excess of the required boron
derivative (1.2 eq.) in a mixture of toluene/ethanol (1.6/1) and
saturated aqueous solution of NaHCO3 in presence of Pd(PPh3)4
(10%). The reactions were run in a sealed tube under microwave
irradiation at 150 ꢁC for 15 min [30]. Compounds 5 (R ¼ OCH3), 6
(R ¼ CN) and 7 (R ¼ SO2CH3) were respectively obtained in 78%, 70%
and 72% yields.
Deprotection of the indolic nitrogen atom was accomplished
with TBAF in refluxing THF and led to 8e10 respectively in excellent
yields. Methyl ether deprotections were performed at r.t. with BBr3
in dichloromethane. The amounts of Lewis acid and the reaction
times were adapted in each case and the final derivatives 11e13
were obtained in satisfactory yields. All the NMR, IR and HMRS
spectral data are in agreement with the structure of the synthesized
indole derivatives 8e10.
2. Chemistry
2.1. Synthesis of (2-indoyl)-(pyridine or pyrazine)-phenyl V-shaped
molecules
The pyrazine analogs of 11e13 were obtained from the chlor-
opyrazine 14, which was obtained from 2-stannylindole 3 and 2,6-
dichloropyrazine via our previously reported Stille type reaction in
98% yield (Scheme 2). Next, a Suzuki reaction of 14 with the 4-
The 1-phenylsulfonyl-6-methoxyindole [29] 2 was obtained
from 3-methoxyaniline 1 via a modified Bischler reaction which
offered the advantage of yielding 2 ready to be regioselectively
functionalized in position C-2 by lithiation (LDA 1.5 eq.) followed by
R
Y
Y
Y
L
X
SnBu3
SO2Ph
R1
N
X
Y
III R, R1 = H, OBn, OMe
NH
II X = Cl or Br
Y = CH or N
R2
R
R1
I
R2
R 2
R, R1 = H, OH, OBn, OMe
Y = CH, N
R2 = OBn, OH,CN, SO2CH3
B(OH)2
H2N
L = C-C or C-NH-C bonds
IV R2 = OMe, CN,SO2Me
Fig. 2. Indole V-Shaped library.
IV R2 = OMe,OH, OBn

5418
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
Br
c
a
R
N
NH2
N
OCH3
b
N
OCH3
OCH3
SO2C6H5
SO2C6H5
1
4
2 R = H
3 R = SnBu3
R2
R2
R2
e
d
f
4
N
N
H
N
N
OCH3
OCH3
N
N
HO
SO2C6H5
H
8 R2 = OCH3
9 R2 = CN
5 R2 = OCH3
11 R2 = OH
6 R2 = CN
12 R2 = CN
10 R2 = SO2CH3
7 R2 = SO2CH3
13 R2 = SO2CH3
Scheme 1. Reagents and conditions : a) Bischler procedure i) C6H5SO2Cl, pyridine, CH2Cl2, 98%, ii) NaHCO3, DMF, BrCH2CH(OC2H5)2, 100 ꢁC, 86%, iii) BF3.Et2O, CH2Cl2, 0 ꢁC, 10 min,
97%; b) C-2 functionalization procedure i) LDA, THF, ꢀ20 ꢁC 30 min, ii) Bu3SnCl, ꢀ78 ꢁC to r.t, 2 h 75%; c) CuI (10%), Pd(PPh3)4 (5%), THF, 3,5-dibromopyridine (1.1 eq.),
mWave,
100 ꢁC, 20 min, 99%; d) 4-substituted phenylboronic acid (1.3 eq.), aq. NaHCO3, toluene/EtOH, Pd(PPh3)4 (10%), Wave, 150 ꢁC, 15 min, 5 78%, 6 70%, 7 72%; e) Bu4NF (1.5 eq.), THF,
m
reflux, from 5 : 6 h, 8 97%, from 6 : 6 h, 9 86%, from 7 : 15 h, 10 99%. f) CH2Cl2, 0 ꢁC to r.t., from 8 : BBr3 (3.0 eq.), 6 h, 11 72%, from 9: BBr3 (1.5 eq.),12 h, 12 58%, from 10 : BBr3 (2.0 eq.),
3 h, 13 53%.
substituted (OMe, CN, SO2CH3) phenylboronic acids led to
compounds 15e17 respectively in 72%, 73% and 65% yields. Removal
of the benzenesulfonyl indolic protections followed by methyl
ether cleavages led to compounds 21e23 in satisfactory yields.
In a previous paper, we reported the preparation of the stannyl
derivative 24 and under classical thermal activation the derivative
25 [23]. Here we report as a new result that the reaction of 24 with
the 2,6-dichloropyrazine led under microwave irradiation to the
targeted compound 26. The two derivatives 25 and 26 were used to
build a new library of final V-shaped compounds 27e31 by Suzuki
cross coupling reactions in good yields; the two deprotection steps
led successively to 32e36 and next to the original final compounds
37e41 (Scheme 3 and Tables 1 and 2).
instead of 3,5-dibromopyridine. The reaction was carried out with
stannyl derivatives 3 and 24 to afford compounds 42 and 43 in good
yields. As expected, we observed exclusively a mono reaction at the
C-2 position of the pyridine ring. Suzuki reaction of 42 and 43 with
4-methoxyphenylboronic acid led respectively to 44 (77% yield)
and 45 (79% yield). The further deprotection of the indolic nitrogen
atoms afforded compounds 46 and 47 in 80% yield while the
cleavage of ethers completed the synthesis, affording the final
derivatives 48 and 49 in nearly quantitative yields.
2.2. Synthesis of (2-indoyl)-(pyridine or pyrazine)-(aminophenyl)-
V-shaped molecules
To obtain information about the interactions of heteroatoms
with the kinase ATP active site, we used 2,4-dichloropyridine
In order to give more flexibility to the tri-aromatic V-shaped
structure, we then sought to introduce on the pyridine or pyrazine
R2
R2
Cl
N
a
N
b
c
N
3
N
N
OCH3
N
N
N
H
OCH3
N
OCH3
SO2C6H5
SO2C6H5
14
18 R2 = OCH3
15 R = OCH3
16 R = CN
17 R = SO2CH3
19 R2 = CN
20 R2 = SO2CH3
R2
21 R2 = OH
N
18 R2 = OCH3
19 R2 = CN
d
22 R2 = CN
23 R2 = SO2CH3
N
N
20 R2 = SO2CH3
HO
H
Scheme 2. Reagents and conditions : a) CuI (10%), Pd(PPh3)4 (5%), THF, 2,6-dichloropyrazine (1.0 eq.),
NaHCO3, toluene/EtOH, Pd(PPh3)4 (10%),
Wave, 150 ꢁC, 15 min, 15 72%, 16 73%, 17 65%; c) Bu4NF (1.5 eq.), THF, reflux, 15 h, 18 88%, 19 88%, 20 99%. d) CH2Cl2, 0 ꢁC to r.t., from 18 : BBr3
(3.0 eq.), 10 h, 21 73%, from 19 : BBr3 (5.0 eq.), 5 h, 22 63%, from 20 : BBr3 (5.0 eq.), 5 h, 23 42%.
m
Wave, 100 ꢁC, 20 min, 98%; b) 4-substituted phenylboronic acid (1.3 eq.), aq.
m

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5419
R2
X
OBn
OBn
OBn
Y
Y
b
a
SnBu3
SO2C6H5
N
N
N
N
N
SO2C6H5
SO2C6H5
24
27-28 Y = CH
25 X = Br, Y = CH
26 X= Cl, Y = N
29-31 Y = N
R2
HO
Y
c, d
32-33 and 37-38 Y = CH
34-36 and 39-41 Y = N
27-28 Y = CH
29-31 Y = N
N
N
H
Scheme 3. Reagents and conditions : a) 3,5-dibromopyridine or 2,6-dichloropyrazine (1.05 eq.), CuI (10%), Pd(PPh3)4 (5%), THF, m
Wave, 100 ꢁC, 20 min, 25, 89% 26, 83%; b) 4-
substituted phenylboronic acid (1.3 eq.), aq. NaHCO3, toluene/EtOH, Pd(PPh3)4 (10%), see Table 1; c) THF, reflux, see Table 2; d) CH2Cl2, 0 ꢁC to r.t., see Table 2.
Table 1
As we were interested in hydroxyl substituents on indole and
aniline due to previous results on CDK inhibition [23], we envisaged
Cross-coupling reactions of compounds 25 or 26 leading to 27e31.
Entry
Y
R2
Time
D or M.W
Product
Yield (%)
catalytic hydrogenolysis as
a
deprotective method. The
6-benzyloxy-1-phenylsulfonyl indole was therefore prepared and
stannylated in the same way as described for compound 3, to give
56. A Stille reaction with 2,6-dichloropyrazine led to the chlor-
opyrazine 57. A Buchwald reaction was then carried out using
bromo derivative 25 and 4-hydroxyaniline or 57 and 4-
benzyloxyaniline to yield respectively 58 and 59 in 80% and 87%
yield. Deprotection of the nitrogen indole atom was achieved in
both cases with Bu4NF and led to 61 in 75% yield but sensitivity of
the 4-aminophenol residue on 58 in basic media led to 60 in only
37% yield. Unfortunately in all cases the envisioned hydrogenolysis
reaction failed (no reaction or degradation).
1
2
3
4
5
CH
CH
N
N
N
CN
4 h
8 h
30 min
30 min
30 min
reflux
reflux
M.W, 150 ꢁC
M.W, 150 ꢁC
M.W, 150 ꢁC
27
28
29
30
31
76
96
78
90
82
SO2CH3
OCH3
CN
SO2CH3
ring a “kneecap” through a 4-hydroxyaniline moiety. To achieve
this, the BuchwaldeHartwig reaction was used [31]. It was first
performed on the bromo derivative 25 with 4-methoxyaniline
using potassium carbonate, Pd(OAc)2, Xantphos in dioxane under
microwave irradiation for 1 h at 140 ꢁC [32]. Under these classical
conditions, compound 50 was obtained in 87% yield. Similarly, 51
and 52 were obtained from the chloro derivatives 26 and 14 in 83%
and 86% yields respectively. Deprotection with Bu4NF (10.0 eq.) was
achieved in refluxing THF (12e15 h) to afford the pyrazine deriv-
atives 54 and 55 respectively in 99% and 86% yield; curiously the
pyridine derivative 50 did not react at all in these conditions and
required the use of 1.5 eq of NaOH (2 M) in refluxing methanol to
afford the deprotected derivative 53 in 70% yield. Unfortunately,
whatever the method used (BBr3, HBr/acetic acid or NaI/TMSCl), we
were unable to cleave the benzyl or the methyl ether bonds of
compounds 53e55.
3. Kinase inhibitions
We evaluated 13 final compounds on 3 types of kinases CDK5,
GSK3 and DYRK1A (Table 3). In a previous paper [23] we reported
the activity of our reference compound C which inhibited 50% of
CDK5 activity at a 1.5 mM and appeared to be 26 times more active
against this kinase versus GSK3 (Table 3, entry 0).
The 4-hydroxy substituent (donor and acceptor of H-bond) in
the phenyl ring seems to be the best to interact with the ATP
binding site of CDK5, while the presence of a substituent able to
Table 2
Deprotection steps leading to 32e36.
Entry
Y
R2
Starting
Material
for step c
Bu4NF
(eq.)
Time
Product,
yield
BBr3
(eq.)
Time
Product after
step d, yield
1
2
3
4
5
CH
CH
N
N
N
CN
27
28
29
30
31
1.5
1.5
3.0
3.0
3.0
4 h
4 h
6 h
12 h
10 h
32, 73%
33, quant
34, 96%
35, 76%
36, 94%
1.1
1.5
11.8
10.0
6.0
4 h
6 h
15 h
12 h
7 h
37, 71%
38, 58%
39a, 99%
40, 99%
41, 41%
SO2CH3
OCH3
CN
SO2CH3
a
R2 ¼ OH.

5420
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
OCH3
Cl
R
R
b
a
3 or 24
R1
N
R1
N
N
N
SO2C6H5
SO2C6H5
42 R = OBn, R1 = H
43 R = H, R1 = OCH3
44 R = OBn, R1 = H
45 R = H, R1 = OCH3
OCH3
OH
R
c
d
R
44 R = OBn, R1 = H
45 R = H, R1 = OCH3
R1
N
H
N
R1
N
N
H
46 R = OBn, R1 = H
48 R = OH, R1 = H
47 R = H, R1 = OCH3
49 R = H, R1 = OH
Scheme 4. Reagents and conditions
methoxyphenylboronic acid (1.5 eq.), aq. satd NaHCO3, toluene/EtOH, Pd(PPh3)4 (10%),
THF, reflux, from 44: 12 h, 46, 80%, from 45 : 4 h, 47, 80%; d) CH2Cl2, 0 ꢁC to r.t., from 46: BBr3 (8.0 eq.), 12 h, 48, 99%, from 47: BBr3 (5.0 eq.), 5 h, 49, 97%.
:
a) 3 or 24 and 2,4-dichloropyridine (1.5 eq.), CuI (10%), Pd(PPh3)4 (5%), THF,
m
Wave, 100 ꢁC, 30 min, 42, 72% or 43, 70%; b) 4-
m
Wave, 150 ꢁC, from 42 : 30 min, 44, 77%, from 43 : 40 min, 45, 79%; c) Bu4NF (3.0 eq.),
X
NH
OCH3
NH
OCH3
Y
Y
Y
a
b or c
R
R
R
N
N
N
N
N
H
N
SO2C6H5
SO2C6H5
53 Y = CH, R = 5-OBn
54 Y = N, R = 5-OBn
55 Y = N, R = 6-OMe
25 X = Br, Y = CH, R = 5-OBn
26 X= Cl, Y = N, R = 5-OBn
14 X = Cl, Y = N, R = 6-OMe
50 Y = CH, R = 5-OBn
51 Y = N, R = 5-OBn
52 Y = N, R = 6-OMe
Cl
N
d
SnBu3
N
OBn
N
N
OBn
SO2C6H5
SO2C6H5
56
57
H
N
R1
NH
R1
N
N
e
c or f
26, 57
R
R
N
H
N
N
N
SO2Ph
60 R = 5-OBn, R1 = OH
61 R = 6-OBn, R1 = OBn
58 R = 5-OBn, R1 = OH
59 R = 6-OBn, R1 = OBn
Scheme 5. Reagents and conditions: a) p-anisidine (1.5 eq.), K2CO3 (2.0 eq.), Pd(OAc)2 (10% mol), Xantphos (20% mol), dioxane,
(1.5 eq.), MeOH/H2O, rflx, 12 h, from 50: 53, 70%; c) Bu4NF (10.0 eq.), THF, 12 h, reflux, 54 99%, 55 86%, from 59: 10 h, 61 75%; d) 2,6-dichloropyrazine (1.2 eq.), CuI (10%), Pd(PPh3)4
(5%), THF,
Wave, 100 ꢁC, 30 min, 57, 91%; e) Pd(OAc)2 (10% mol), Xantphos (20% mol), dioxane, Wave, 140 ꢁC, 1 h, from 26 : 4-hydroxyaniline (1.5 eq.), K2CO3 (2.0 eq.), 58 87%, from
57 : 4-benzyloxyaniline (1.5 eq.), K2CO3 (3.0 eq.), 59 80%. f) Bu4NF (4.0 eq.), THF, rflx, 8 h, 60 37%.
m
Wave, 140 ꢁC, 1 h, 50 87%, 51 83%, 52 86%; b) NaOH
m
m
accept only H-bonds of the SO2CH3 and CN type (entries 1, 2)
reduces drug/enzyme interactions. The same result was observed
by changing the central pyridine ring by the less basic pyrazine
despite its ability to give an additional hydrogen bond with the
kinase active site (entries 3e5). Fortunately, varying the position of
the hydroxyl group on the indole core increases the activity on
CDK5; the 6-hydroxy indole series gave better inhibition (in the sub
micromolar range) for the same substituents (OH, SO2CH3, CN).
Compound 11 (IC50 ¼ 160 nM) is 10 fold more active than derivative
C, leading to a new V-shaped kinase inhibitor lead.
The pyridine derivatives 32, 38 and 11e13 appeared to be more
efficient than their pyrazine analogs 40, 41 and 21e23. This analysis
showed an increase in activity by a factor of 5e10 except for the
compounds reference C and 39 which affected CDK5 in a similar

Table 3
DYRK1A, CDK5 and GSK3 inhibitions.
manner. In addition, with 2,4-disubstituted pyridine compounds 48
and 49 (IC50 ¼ 360 and 830 nM respectively, entries 12, 13), inhi-
bition of the enzyme was always better than in the pyrazine series
but lower than in the 3,5-disubstituted pyridine series. A higher
basicity of the pyridine compared to the pyrazine ring and the
optimal position of the nitrogen atom may explain these differ-
ences and this weaker ability of forming H-bonds with the active
site.
Entry
Compounds
IC50 (mM)
DYRK1A
CDK5
GSK3
40
b
0
C
ND
1.5
Selectivity in kinase inhibition was next measured on the GSK3
and DYRK1A [33], two kinases involved mainly in neurodegenera-
tive disorders such as Alzheimer’s disease and mental retardation.
In all cases our derivatives are selective for CDK versus GSK3b(ex-
cept 22 and 23). Nevertheless, interesting results were obtained by
performing tests on DYRK1A. Our lead derivative 11 is very active
and a noteworthy IC50 ¼ 60 nM was measured. This new inhibition
is sensitive to the same structure modifications depicted by the
CDK SAR studies.
b
1
2
32
3.3
2.3
5.3
1.8
> 100
38
7.3
3
4
39
40
0.34
1.5
4.4
4.7
26
4. Molecular modeling
In order to explain the inhibition results obtained with our
synthesized compounds, and more specifically with our lead
derivative 11, we focused molecular modeling studies on DYRK1A
and docking studies were carried out. The crystal structure of
DYRK1A in complex with 7-methoxy-1-methyl-9H-pyrido[3,4-b]
indole currently named HRM (PDB code 3ANR) was chosen to study
the binding mode of our active compounds [34,35]. First of all, HRM
was docked again to reproduce the co-crystal complex. Superim-
position of the best docked pose, i.e. the top score conformer, on the
crystal structure fits well between the two structures: this initial
step of rigid docking gave an RMSD deviation, based on heavy
atoms, of 0.12 Å.
Next all the ligands (14 compounds, Table 3) were docked using
the previously validated protocol. All the compounds adopted
conformations within the binding site positioning the pyridine ring
(or pyrazine ring) near the hinge region (Leu241, Met240, Glu239),
allowing H-bond interactions with the protein through a nitrogen
atom. The ligands interacted by means of H-bonds with two other
regions of the protein. The first one corresponds to solvent access
(H-bond with Asp247) and the second one is named pocket 1 (H-
bond with Lys188 and Glu203). Thus, regarding the other parts of
our compounds, two modes of binding were observed, excepted for
compounds 38, 41, 13 and 23 which preferred only binding mode 1
(Fig. 3).
1
5
41
3.1
6.3
26
6
7
11
12
0.06
1.6
0.16
0.9
1.1
4
8
13
0.35
0.38
1.1
9
21
22
0.54
1.5
5.4
5.3
5.7
These two binding modes are illustrated with the most active
compound 11 (Fig. 3) which inhibited DYRK1A in the nanomolar
range. Binding mode 1 (left pose) described mainly H-bond inter-
actions between the 6- or 5-hydroxy substituent on the indole
moiety in pocket 1 whereas the 4-phenol ring pointed in the
direction of the solvent toward Asp247.
10
5
Left: binding mode 1 where the substituted phenyl ring points to
the solvent. Right: binding mode 2 where hydroxyindole points to
the solvent. Only polar hydrogen atoms are represented for clarity.
H-bonds are shown in dashed yellow lines.
11
12
13
23
48
49
2.7
2.6
2.3
ND
ND
In binding mode 2 (right pose), the indole group of 11 pointed to
the solvent whereas the substituted phenyl ring found an optimal
interaction in pocket 1. Similar crucial H-Bond interactions, as for
binding mode 1, were found between the drug and the enzymatic
active site. Steric hindrance on the phenyl ring could impose the
orientation of the synthesized compounds to the solvent. This
could be the case with methylsulfonyl containing derivatives 38, 41,
13 and 23. It should also be mentioned that varying substituents on
the phenyl ring decreases activity but does not result in a total lack
of activity. This could be in favor of binding mode 1 where
0.23
0.3
0.36
0.83

5422
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
Fig. 3. The two binding modes of compound 11 observed in the active site of DYRK1A.
substituents point to the solvent, limiting modifications in the
proteineligand interactions.
7. Experimental section
7.1. Chemistry
5. Cell effects
1H-NMR and 13C-NMR spectra were recorded on a Bruker DPX
250 or 400 MHz instrument using CDCl3 or DMSO-d6. The chemical
shifts are reported in ppm (d scale) and all coupling constants (J)
As the optimization of our V-shaped scaffold led to more effi-
cient kinase inhibitors than reference C, we studied their effects on
cells. In a previous paper we showed that compound C inhibits cell
values are in hertz (Hz). The splitting patterns are designated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
and dd (doublet doublet). Melting points are uncorrected. IR
absorption spectra were obtained on a Perkin Elmer PARAGON
1000 PC and values were reported in cmꢀ1. MS spectra (Ion Spray)
were performed on a Perkin Elmer Sciex PI 300. HMRS were per-
formed by the Centre Commun de Spectrométrie de Masse (Cler-
mont-Ferrand, France). Monitoring of the reactions was performed
using silica gel TLC plates (silica Merck 60 F254). Spots were visu-
alized by UV light at 254 nm and 356 nm. Columns chromatography
were performed using silica gel 60 (0.063e0.200 mm, Merck).
Microwave experiments were performed on a Biotage Initiator
apparatus.
survival in a micromolar range (CEM Cells IC50 ¼ 4.6
mM) [23]. To
evaluate the potency of the 13 new V-shaped compounds we now
used 6 representative tumoral cell lines of liver (Huh7), colon (Caco,
HCT116), breast (MDA-MB 231), prostate (PC3), lung (NCI) and one
normal cell line (fibroblasts) and measured survival. Results are
reported in Table 4.
Observation of the biological material in presence of our V-
shaped indole molecules showed a clear cytostatic effect but the
cells could not be induced to enter in apoptosis. This effect is
currently associated with a kinase functioning disorder. Our
derivatives possess good cell penetration parameters but their
efficiency on the signaling pathway was not sufficient to induce
strong cell death. Our newly identified CDK5 inhibitors (i.e. 11e13,
48, 49) were globally more efficient than Roscovitin and exhibited
a similar cell profile to C.
The most active compounds were clearly the pyridine deriva-
tives 12, 13 and 48 (entries 7, 8, 12) with 50% of survival at only
1.5e2 mM range and selectivity for particular cell lines. Compound
12 was the most interesting molecule, even if its effect on CDK5 was
limited. In this case, a higher preference for liver Huh7 cells without
any effect on normal cells was observed. Since the effect on the
diploid cell line is much weaker than on abnormal cells, our new
library possesses the criteria for further developments as non toxic
agents.
7.1.1. General procedure A for Stille cross coupling reaction
A solution of the stannylated indole derivative, the corre-
sponding halogenated derivative (1.2 eq) and CuI (0.1 eq) in THF
was degassed under vigorous stirring by argon bubbling for 20 min.
Pd(PPh3)4 (5 or 10% mol/stannylated indole) was added. The
reaction mixture was irradiated in a microwave oven for the indi-
cated time. After cooling, water was added and the crude product
was extracted with EtOAc. The combined organic layers were
successively washed with brine, dried with MgSO4 and filtered off.
The solvents were removed under reduced pressure and the crude
material was purified by flash chromatography.
7.1.2. General procedure B for Suzuki cross coupling reaction
The phenylboronic acid derivative (1.3 eq.) was added to
a solution of the halogenated pyridine (pyrazine) derivative in
a mixture of toluene, ethanol, and aqueous saturated NaHCO3
solution. The reaction mixture was then degassed under vigorous
stirring by argon bubbling for 20 min. Pd(PPh3)4 (10% mol/halo-
genated derivatives) was added and the mixture immediately
transferred in a pre-heated oil bath and refluxed for the indicated
time or irradiated in a microwave oven. After cooling, water was
added and the crude product was extracted with EtOAc. The
combined organic layers were washed with brine, dried with
MgSO4 and filtered off. The solvents were removed under reduced
pressure and the crude material was purified by flash chromatog-
raphy. In the NMR assignments the exponent ‘ refers to pyridine or
pyrazine hydrogens (central ring B) and exponent “ refers to phenyl
hydrogens (C ring).
6. Conclusion
We have reported here the synthesis and biological evaluation
of a new V-shaped library including 3-[(2-indolyl)]-5-phenyl-3,5-
pyridine,
3-[(2-indolyl)]-5-phenyl-2,4-pyridine
and
3-[(2-
indolyl)]-5-phenyl-2,6-pyrazine derivatives, and have identified
their biological effects. We successfully used Stille or Suzuki type
reactions to create CeC bonds. Kinase and cell effects were
measured on 13 new derivatives and compared with our reference
I. Cancer cell lines are always targeted by the V-shaped derivatives
in the
Results in kinase assays show that compound 11 inhibited CDK5 at
M for I). A good selectivity over
mM range in adequacy with the strength of kinase inhibition.
IC50 ¼ 160 nM range (versus 1.5
m
GSK3 is maintained. Additionally compound 11 was also identified
as a new lead for DYRK1A inhibitor discovery (IC50 ¼ 60 nM).

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5423
Table 4
Cell effects.
Entry
Compounds
Cell lines IC50
Huh7
(mM)
Caco
MDA-MB 231
12
HCT 116
9
PC3
NCI
Fibroblasts
1
32
38
7
10
5
20
>25
>25
2
15
12
15
8
6
25
3
4
39
40
8
8
3
9
3
6
6
3
3
5
7
5
15
5
5
41
4
3
4
2.5
10
15
25
6
7
8
11
12
13
3
6
10
3
20
12
5
3
6
2
6
7
4
20
25
7
>25
25
3
1.5
3
9
21
5
7
10
3
5
4
20
10
11
22
23
7
7
15
13
6
9
13
12
8
9
25
25
10
20
12
13
48
49
3
5
4
3
6
1.5
5
10
20
2
12
8
15
12
14
15
Roscovitin
DMSO
10
>25
10
>25
15
>25
8
>25
8
>25
20
>25
>25
>25

5424
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
7.1.3. General procedure C for deprotection of methoxy or benzyloxy
ethers
The solvents were removed under reduced pressure and the crude
materiel was purified by flash chromatography (petroleum ether),
compound 3 was obtained as colorless oil (1.50 mg, 75%). Rf: 0.62
A solution of BBr3 (1 M in CH2Cl2, for the number of equivalents,
see below) was added dropwise to a solution of methoxylated or
benzyloxy compound in CH2Cl2 at 0 ꢁC. The stirring was continued
for the indicated time at room temperature. The reaction mixture
was then poured over ice and extracted with EtOAc. The organic
layer was dried with MgSO4, and filtered off. The solvents were
removed under reduced pressure and the crude material was
purified by flash chromatography.
(petroleum ether/EtOAc 80/20); IR (ATR Diamond, KBr, cmꢀ1
) n
2957, 2931, 2853, 1612, 1486, 1360, 1277, 1202, 1169, 1158, 1122, 824,
722; 1H NMR (CDCl3, 250 MHz)
d
0.89 (t, 9H, J ¼ 7.5 Hz, 3 ꢂ CH3),
1.13e1.19 (m, 6H, 3 ꢂ CH2), 1.26e1.41 (m, 6H, 3 ꢂ CH2), 1.49e1.63
(m, 6H, 3 ꢂ CH2), 3.79 (s, 3H, OCH3), 6.74 (s, 1H, H3), 6.82(dd, 1H,
J ¼ 8.8 Hz, J’ ¼ 2.5 Hz, H5), 7.34e7.41 (m, 4H, Harom þ H4 þ H7),
7.47e7.52 (m, 1H, Harom), 7.60e7.63 (m, 2H, Harom); 13C NMR
(CDCl3, 100.6 MHz)
d
11.7 (3 ꢂ CH2), 13.6 (3 ꢂ CH3), 27.3 (3 ꢂ CH2),
7.1.4. General procedure D for deprotection of indolic N-phenylsul-
fonyl group
28.9 (3 ꢂ CH2), 55.6 (CH3), 98.1 (CH), 112.2 (CH), 120.5 (CH), 120.6
(CH), 125.9 (Cq), 126.2 (2 ꢂ CH), 129.0 (2 ꢂ CH), 133.2 (CH), 139.3
(Cq), 139.4 (Cq), 141.8 (Cq), 157.4 (Cq); MS (ion spray): m/z 577
[M þ H]þ.
A 1 M solution of Bu4NF in THF (for the number of equivalents,
see below) was dropwise added to a solution of protected indole
compound in dry THF. The reaction was refluxed for the indicated
time. After cooling, the mixture was concentrated under reduced
pressure. After hydrolysis with water, the mixture was extracted
with EtOAc, the organic layer washed with brine then dried with
MgSO4, and filtered. The solvents were removed under reduced
pressure and the crude material was purified by flash
chromatography.
7.1.8. 1-Benzenesulfonyl-2-(5-bromo-pyridin-3-yl)-6-methoxy-1H-
indole (4)
Compound 4 was obtained following the general procedure A. A
solution of 1-benzenesulfonyl-6-methoxy-2-tributyl stannyl-1H-
indole
3 (1.0 g, 1.53 mmol), 3,5-dibromopyridine (380 mg,
1.69 mmol) and CuI (29.13 mg, 0.153 mmol) in THF (25 mL) were
used. The reaction mixture was irradiated in a
mWave oven for
7.1.5. General procedure E for BuchwaldeHartwig cross coupling
reaction
20 min at 100 ꢁC. After flash chromatography (petroleum ether/
EtOAc 80/20), compound 4 was obtained as a yellow solid (680 mg,
99%). Rf: 0.28 (petroleum ether/EtOAc 70/30); mp 155e159 ꢁC; IR
A solution of the halogenated derivative, the corresponding amine
(1.5 eq.) and K2CO3 (2.0 eq.) in 1,4-dioxane was degassed under
vigorous stirring by argon bubbling for 20 min. Pd(OAc)2 (10% mol./
halogenated derivative) and Xantphos (20% mol./halogenated deriv-
ative) were then added and the mixture was charged in a microwave
vial equipped with a stirring bar. It was subjected to irradiation for 1 h
at 140 ꢁC. After cooling, water was added and the aqueous layers were
extracted with EtOAc. The combined organic layers were successively
washed with brine (10 mL), dried with MgSO4 and filtered off. The
solvents were removed under reduced pressure and the crude
material was purified by flash chromatography.
(ATR Diamond,KBr, cmꢀ1
)
n
2956, 2923, 2866, 2854, 1606, 1488,
1439, 1371, 1272, 1170, 1105, 836, 726, 684;1H NMR (CDCl3,
250 MHz)
d 3.94 (s, 3H, OCH3), 6.58 (s, 1H, H3), 6.93 (dd, 1H,
J ¼ 2.3 Hz, J0 ¼ 8.8 Hz, H5), 7.28e7.39 (m, 5H, Harom), 7.45e7.51 (m,
1H, H4), 7.85 (d, 1H, J ¼ 2.0 Hz, H7), 7.99 (s, 1H, H40), 8.55 (br s, 1H,
H20), 8.70 (br s, 1H, H60); 13C NMR (CDCl3, 100.6 MHz)
d 55.8 (CH3),
100.7 (2 ꢂ CH), 114.0 (CH), 115.5 (CH), 121.7 (CH), 123.8 (Cq), 126.5
(2 ꢂ CH), 128.9 (2 ꢂ CH), 133.9 (2 ꢂ CH), 137.1 (Cq), 139.7 (Cq), 140.0
(CH), 143.0 (Cq), 150.3 (Cq), 158.7 (2 ꢂ Cq); HRMS (EI-MS): calcu-
lated for C20H16 N2O3S79Br 312.1137 found 312.1148.
7.1.6. N-Phenylsulfonyl-6-methoxy-1H-indole (2) [29]
7.1.9. 1-Benzensulfonyl-6-methoxy-2-[5-(4-methoxy-phenyl)-
pyridin-3-yl]-1H-indole (5)
To a solution of N-(2,2-diethoxyethyl)-N-(3-methoxyphenyl)-
benzene-sulfonamide (188 mg, 0.49 mmol) in CH2Cl2 (7 mL),
Compound 5 was obtained following the general procedure B.
Compound 4 (500 mg,1.12 mmol)and4-methoxyphenylboronic acid
(221.25 mg, 1.45 mmol), in a mixture of toluene (51.5 mL), ethanol
(26.5 mL) and aqueous saturated NaHCO3 solution (17 mL) were
BF3.Et2O (93.5 m
L, 0.74 mmol) was added dropwise at 0 ꢁC under
argon. After 15 min, an aqueous saturated solution of NaHCO3
(10 mL) was added and the crude product was extracted with
CH2Cl2 (2 ꢂ 10 mL). The combined organic layers were successively
washed with brine (5 mL), dried with MgSO4 and filtered off. The
solvents were removed under reduced pressure and the crude
material was purified by recrystallization from dichloromethane/
MeOH 90/10 to afford compound 2 as a colorless solid (686 mg,
97%). Rf: 0.6 (petroleum ether/EtOAc 60/40); mp 133 ꢁC;1H NMR
used. The reaction was realized in a m
Wave oven for 15 min at 150 ꢁC.
Flash chromatography (petroleum ether/EtOAc 60/40) afforded
compound 5 as a yellow solid (411 mg, 78%). Rf: 0.13 (ꢀp1etroleum
ether/EtOAc 60/40); Mp 156 ꢁC; IR (ATR Diamond,KBr, cm
) n 3856,
3653, 2963, 2370, 1608, 1512, 1432, 1372, 1245, 1181, 1027, 834, 751,
726, 689; 1H NMR (CDCl3, 250 MHz)
d
3.88 (s, 3H, OCH3), 3.95 (s, 3H,
(CDCl3, 250 MHz)
d
3.87 (s, 3H, OCH3), 6.58 (d, 1H, J ¼ 5.0 Hz, H3),
OCH3), 6.60 (s, 1H, H3); 7.68 (dd, 1H, J ¼ 8.8 Hz, J0 ¼ 2.3 Hz, H5), 7.04
(d, 2H, J ¼ 10.0 Hz, 2 ꢂ H300), 7.25e7.39 (m, 5H, Harom), 7.47 (d, 1H,
J ¼ 7.5 Hz, H4), 7.61 (d, 2H, J ¼ 10.0 Hz, 2 ꢂ H200), 7.90 (d,1H, J ¼ 2.0 Hz,
H7), 8.05 (s, 1H, H40), 8.49 (s, 1H, H20), 8.83 (s, 1H, H60); 13C NMR
6.87 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.5 Hz, H5), 7.38 (d, 1H, J ¼ 8.8 Hz, H4),
7.42e7.47 (m, 3H, Harom), 7.51e7.54 (m, 2H, H2 þ H7), 7.84e7.88
(m, 2H, Harom).
(CDCl3, 100.6 MHz)
d 55.4 (CH3), 55.8 (CH3), 100.8 (CH), 112.5 (Cq),
7.1.7. 1-Benzenesulfonyl-6-methoxy-2-tributylstannyl-1H-indole (3)
To a solution of 1-benzenesulfonyl-6-methoxy-1H-indole 2
(1.0 g, 3.48 mmol) in dry THF (20 mL) under argon at ꢀ20 ꢁC was
added dropwise a solution of LDA in hexane (2 M, 2.78 mL,
5.56 mmol). After 30 min stirring at ꢀ20 ꢁC, the resulting red
solution was cooled to ꢀ78 ꢁC and treated with Bu3SnCl (1.60 mL,
5.91 mmol). The mixture was warmed to room temperature within
2 h under stirring and then hydrolyzed with water (50 mL). The
mixture was extracted with EtOAc (3 ꢂ 50 mL), the combined
organic layers were successively washed with a saturated solution
of KF (50 mL), water (50 mL) then dried with MgSO4, and filtered.
113.8(CH), 114.7 (3 ꢂ CH), 121.5 (2 ꢂ CH), 124.0 (2 ꢂ Cq), 126.5
(2 ꢂ CH), 128.4 (3 ꢂ CH), 128.8 (2 ꢂ CH), 129.7 (Cq), 133.8 (2 ꢂ CH),
137.3 (Cq), 139.8 (Cq), 158.4 (Cq), 159.9 (2 ꢂ Cq); HRMS (EI-MS): m/z
calculated for C27H22 N2O4S 471.1379 found 471.1368.
7.1.10. 4-[5-(1-Benzenesulfonyl-6-methoxy-1H-indol-2-yl)-pyridin-
3-yl]-benzonitrile (6)
Compound 6 was obtained following the general procedure B.
Compound 4 (400 mg, 0.9 mmol) and 4-cyanophenylboronic acid
(171.9 mg, 1.17 mmol) in a mixture of toluene (42 mL), ethanol
(21.3 mL) and aqueous saturated NaHCO3 solution (13.6 mL) were

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5425
used. The reaction mixture was realized in a
m
Wave oven 15 min at
86%). Rf: 0.30 (petroleum ether/EtOAc 50/50); mp 210 ꢁC; IR (ATR
Diamond, cmꢀ1
3706, 2222, 1597, 1646, 1291, 1260, 1200, 1159,
1036, 829; 1H NMR (CDCl3, 250 MHz)
3.87 (s, 3H, OCH3), 6.84 (dd,
150 ꢁC. Flash chromatography (petroleum ether/EtOAc 70/30)
afforded compound 6 as a yellow solid (298 mg, 70%). Rf: 0.57
(petroleum ether/EtOAc 60/40); mp 106 ꢁC; IR (IR (ATR Diamond,
) n
d
1H, J ¼ 8.5 Hz, J’ ¼ 1.8 Hz, H5), 6.91 (s, 2H, H3 þ H7), 7.53 (d, 1H,
J ¼ 8.8 Hz, H4), 7.73 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H300), 7.79 (d, 2H,
J ¼ 8.0 Hz, 2 ꢂ H200), 7.89 (d, 1H, J ¼ 1.7 Hz, H40), 8.58 (s, 1H, NH),
cmꢀ1 2226, 1610, 1117; 1H NMR (CDCl3, 250 MHz)
) n d 3.96 (s, 3H,
OCH3), 6.64 (s, 1H, H3), 6.95 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.3 Hz, H5),
7.30e7.38 (m, 5H, Harom), 7.49 (d, 1H, J ¼ 7.0 Hz, H4), 7.80 (br s, 4H,
2 ꢂ H300 þ 2 ꢂ H200), 7.89 (d,1H, J ¼ 2.0 Hz, H7), 8.16 (t,1H, J ¼ 2.0 Hz,
H40), 8.62 (s, 1H, H20), 8.87 (s, 1H, H60); 13C NMR (CDCl3, 100.6 MHz)
8.71 (s,1H, H20), 8.94 (s,1H, H60);13C NMR (CDCl3,100.6 MHz)
d 55.6
(CH3), 99.4 (CH), 101.9 (CH), 110.9 (CH), 112.1(Cq), 118.5 (Cq), 121.7
(CH), 123.2 (Cq), 127.9 (2 ꢂ CH), 128.9 (Cq), 130.1 (CH), 132.5(Cq),
132.9 (2 ꢂ CH), 135.0 (Cq), 138.3 (Cq), 142.1 (Cq), 145.7 (CH), 146.2
(CH), 157.4 (Cq); HRMS (EI-MS): m/z calculated for C21H16 N3O
326.1293 found 326.1292.
d
55.8 (CH3),100.9 (CH),112.1 (Cq),113.9 (CH),115.2 (CH),118.5 (Cq),
121.6 (CH), 123.9 (Cq), 126.4 (2 ꢂ CH), 127.9 (2 ꢂ CH), 128.8
(2 ꢂ CH),132.8 (2 ꢂ CH), 133.9 (2 ꢂ CH), 136.1 (Cq), 137.0 (Cq), 137.1
(Cq), 139.8 (Cq), 141.9 (Cq), 147.6 (CH), 148.6 (CH), 158.6 (2 ꢂ Cq);
HRMS (EI-MS): m/z calculated for C27H20 N3O3S 466.1225 found
466.1224.
7.1.14. 2-[5-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-6-methoxy-
1H-indole (10)
Compound 10 was obtained following the general procedure B.
Compound 7 (250 mg, 0.48 mmol) in THF (5 mL) and Bu4NF (1.5
eq, 0.75 mL, 1 M in THF, 0.75 mmol) were used. The reaction was
refluxed for 15 h. Flash chromatography (dichloromethane/MeOH
98/02) afforded compound 10 as a yellow solid (190 mg, 99%). Rf:
0.32 (dichloromethane/MeOH 90/10); mp 86 ꢁC; IR (ATR Dia-
7.1.11. 1-Benzenesulfonyl-2-[5-(4-methanesulfonyl-phenyl)-pyridin-
3-yl]-6-methoxy-1H-indole (7)
Compound 7 was obtained following the general procedure B.
Compound
4 (400 mg, 0.9 mmol) and 4-methanesulfonyl-
phenylboronic acid (216 mg, 1.08 mmol) in a mixture of toluene
(42 mL), ethanol (21.3 mL) and aqueous saturated NaHCO3 solution
mond,cmꢀ1
724;1H NMR (DMSO-d6, 250 MHz)
d
)
n
3730, 2226, 1597, 1292, 1260, 1200, 1154, 1116, 827,
3.30 (s, 3H, SO2CH3), 3.80 (s,
(13.6 mL) were used. The reaction mixture was realized in a
m
Wave
oven for 15 min at 150 ꢁC. Flash chromatography (petroleum ether/
EtOAc 40/60) afforded compound 7 as a yellow solid (333 mg, 72%).
Rf: 0.25 (petroleum ether/EtOAc 40/60); mp 150 ꢁC; IR (IR (ATR
3H, OCH3), 6.71 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.2 Hz, H5), 6.91 (s, 1H,
H3), 7.12 (s,1H, H7), 7.47 (d, 1H, J ¼ 8.8 Hz, H4), 8.09 (d, 2H,
J ¼ 8.7 Hz, 2 ꢂ H300), 8.14 (d, 2H, J ¼ 8.2 Hz, 2 ꢂ H200), 8.53 (s, 1H,
H40), 8.85 (d, 1H, J ¼ 1.0 Hz, H20), 9.11 (d, 1H, J ¼ 1.0 Hz, H60), 11.6
Diamond, cmꢀ1
1H NMR (DMSO-d6, 250 MHz)
)
n
2369, 1366, 1301, 1186, 1149, 1117, 840, 732, 688;
3.30 (s, 3H, SO2CH3), 3.88 (s, 3H,
d
(s, 1H, NH);13C NMR (DMSO-d6, 100.6 MHz)
d 43.4 (CH3), 55.1
OCH3), 6.97 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.3 Hz, H5), 7.06 (s, 1H, H3), 7.47
(m, 7H, Harom), 8.08 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 8.13 (d, 2H,
J ¼ 9.0 Hz, 2 ꢂ H200), 8.32 (s, 1H, H40), 8.78 (d, 1H, J ¼ 1.8 Hz, H20),
(CH3), 100.5 (CH), 110.0 (Cq), 121.1(CH), 122.6 (Cq), 127.6 (CH),
127.8 (CH), 128.6 (2 ꢂ CH), 131.3 (2 ꢂ CH), 131.9 (CH), 133.1(Cq),
133.9 (Cq), 138.2 (Cq), 140.3 (Cq), 141.0 (Cq), 141.8 (CH), 145.7 (CH),
156.3 (Cq); HRMS (EI-MS): m/z calculated for C21H19 N2O3S
379.1116 found 379.1134.
9.03 (d, 1H, J ¼ 2 Hz, H60); 13C NMR (DMSO-d6, 100.6 MHz)
d 43.4
(CH3), 55.5 (CH3), 100.3 (CH), 113.5 (CH), 115.7 (CH), 126.2 (CH),
127.7 (CH), 127.9 (CH), 128.4 (Cq), 128.6 (2 ꢂ CH), 129.5 (CH), 131.4
(2 ꢂ CH), 131.9 (CH), 132.1 (Cq), 132.8 (Cq), 133.1 (Cq), 134.5 (Cq),
135.5 (Cq), 136.3(CH), 138.9 (CH), 140.4 (Cq), 141.6 (Cq), 147.4 (CH),
149.2 (CH), 157.9 (Cq). HRMS (EI-MS): m/z calculated for C27H23
N2O5S2 519.1048 found 519.1056.
7.1.15. 2-[5-(4-Hydroxy-phenyl)-pyridin-3-yl]-1H-indol-6-ol (11)
Compound 11 was obtained following the general procedure C.
A solution of compound 8 (200 mg, 0.6 mmol) in CH2Cl2 (15 mL)
and BBr3 (3.0 eq., 1.8 mL, 1.8 mmol, 1 M in CH2Cl2) were used. The
reaction mixture was stirred for 6 h. After flash chromatography
(CH2Cl2), compound 11 was obtained as a brown solid (115 mg,
72%). Rf: 0.12 (petroleum ether/EtOAc 40/60); mp >250 ꢁC; IR (ATR
7.1.12. 6-Methoxy-2-[5-(4-methoxy-phenyl)-pyridin-3-yl]-1H-
indole (8)
Compound 8 was obtained following the general procedure D.
Compound 5 (350 mg, 0.743 mmol) in THF (10 mL) and Bu4NF (1.5
eq, 1.11 mL, 1.0 M in THF, 1.11 mmol) were used. The reaction was
refluxed for 6 h. Flash chromatography (petroleum ether/EtOAc 60/
40) afforded compound 8 as a white solid (238 mg, 97%). Rf: 0.12
(petroleum ether/EtOAc 50/50); mp 218 ꢁC; IR (ATR Diamond,
Diamond, cmꢀ1
1043, 813, 691; 1H NMR (DMSO-d6, 250 MHz)
) n 3329, 1702, 1592, 1514, 1439, 1246, 1175, 1117,
d
6.56 (d, J ¼ 7.5 Hz,
1H, H4), 6.79 (s, 1H, H3), 6.92 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H300), 6.99 (s, 1H,
H7), 7.34 (d, 1H, J ¼ 10.0 Hz, H5), 7.66 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H200),
8.32 (s, 1H, H40), 8.66 (s, 1H, H20), 8.92 (s, 1H, H60), 9.10 (s, 1H, OH),
9.72 (s,1H, OH), 11.33 (s, 1H, NH); 13C NMR (DMSO-d6, 100.6 MHz)
cmꢀ1
)
n
2924, 1624, 1503, 1456, 1290, 1247, 1164, 1111, 1023, 834; 1H
d
96.2 (CH), 100.0 (CH), 110.4 (CH), 115.9 (2 ꢂ CH),120.8 (CH), 121.8
NMR (CDCl3, 250 MHz)
d
3.88 (s, 6H, 2 ꢂ OCH3), 6.82 (dd, 1H,
(Cq), 127.5 (Cq), 128.1 (CH), 128.1 (2 ꢂ CH), 128.3 (Cq), 132.5
(Cq),135.4 (Cq), 138.5 (Cq), 144.1 (CH), 145.1 (CH), 153.8 (Cq), 157.8
(Cq); HRMS (EI-MS): m/z calculated for C19H15 N2O2 303.1134
found 303.1138.
J ¼ 8.3 Hz, J’ ¼ 2.3 Hz, H5), 6.88 (s, 1H, H3), 6.92 (s, 1H, H7), 7.03 (d,
2H, J ¼ 10.0 Hz, 2 ꢂ H300), 7.52 (d, 1H, J ¼ 7.5 Hz, H4), 7.52 (d, 2H,
J ¼ 10.0 Hz, 2 ꢂ H200), 8.01 (t, 1H, J ¼ 2.0 Hz, H40), 8.42 (br s, 1H, NH),
8.70 (d, 1H, J ¼ 2.0 Hz, H20), 8.83 (d, 1H, J ¼ 2.0 Hz, H60); 13C NMR
(CDCl3, 100.6 MHz)
d
55.4 (CH3), 55.6 (CH3), 94.5 (CH), 101.4 (CH),
7.1.16. 4-[5-(6-Hydroxy-1H-indol-2-yl)-pyridin-3-yl]-benzonitrile
(12)
110.7(CH), 114.6 (2 ꢂ CH), 121.5 (2 ꢂ Cq), 128.3 (3 ꢂ CH), 128.4 (Cq),
129.7 (Cq), 129.7 (CH), 133.4 (Cq), 134.1 (Cq), 136.5 (2 ꢂ Cq), 144.0
(CH), 146.3 (CH); HRMS (EI-MS): m/z calculated for C21H19 N2O2
331.1447 found 331.1451.
Compound 12 was obtained following the general procedure C.
A solution of compound 9 (80 mg, 0.246 mmol) in CH2Cl2 (10 mL)
and BBr3 (1.5 eq., 0.51 mL, 0.37 mmol, 1 M in CH2Cl2) were used.
The reaction mixture was stirred for 12 h. After flash chromatog-
raphy (CH2Cl2/MeOH 95/05), compound 12 was obtained as
a yellow solid (45 mg, 58%). Rf: 0.4 (CH2Cl2/MeOH 90/10); mp
7.1.13. 4-[5-(6-Methoxy-1H-indol-2-yl)-pyridin-3-yl]-benzonitrile (9)
Compound 9 was obtained following the general procedure D. A
solution of compound 6 (200 mg, 0.43 mmol) in THF (5 mL) and
Bu4NF (1.5 eq, 0.65 mL, 1 M in THF, 0.65 mmol) were used. The
reaction was refluxed for 6 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 9 as a yellow solid (120 mg,
220 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
3433, 3335, 2234, 1627, 1594,
6.57 (d, 1H,
1443, 1244, 1219, 1142, 821;1H NMR (CDCl3, 250 MHz)
d
J ¼ 8.3 Hz, H5), 6.80 (s, 1H, H3), 7.06 (s, 1H, H7), 7.36 (d, 1H,
J ¼ 8.5 Hz, H4), 8.03 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H300), 8.08 (d, 2H,

5426
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
J ¼ 7.5 Hz, 2 ꢂ H200), 8.50 (s, 1H, H40), 8.82 (s, 1H, OH), 9.11 (s, 1H,
H50);13C NMR (CDCl3, 100.6 MHz)
d 55.4 (CH3), 55.8 (CH3), 100.4
H20), 9.10 (s, 1H, H60), 11.37 (s, 1H, NH);13C NMR (CDCl3, 100.6 MHz)
(CH), 112.9 (Cq), 113.8 (CH), 114.4 (2 ꢂ CH), 116.2 (CH), 116.9 (Cq),
122.1 (CH), 123.9 (Cq), 127.0 (2 ꢂ CH), 128.4 (Cq), 128.5 (2 ꢂ CH),
128.8 (2 ꢂ CH), 129.5 (Cq), 133.6 (CH), 136.8 (Cq), 137.4 (Cq), 139.6
(Cq), 139.8 (CH), 143.2 (CH), 158.8 (Cq); HRMS (EI-MS): m/z calcu-
lated for C26H22 N3O4S 472.1331 found 472.1348.
d
96.1 (CH), 99.5 (CH), 110.5 (Cq), 110.8 (Cq), 118.7 (Cq), 120.9 (CH),
121.8 (CH), 127.8 (2 ꢂ CH), 128.6 (Cq), 129.2 (CH), 132.0 (Cq), 132.9
(2 ꢂ CH), 133.7 (Cq), 138.6 (CH), 141.5 (CH), 145.3 (Cq), 145.6 (CH),
154.0 (Cq); HRMS (EI-MS): m/z calculated for C20H14 N3O 312.1137
found 312.1135.
7.1.20. 4-[6-(1-Benzenesulfonyl-6-methoxy-1H-indol-2-yl)-pyrazin-
2-yl]-benzonitrile (16)
7.1.17. 2-[5-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-1H-indol-6-
ol (13)
Compound 16 was obtained following the general procedure B.
Compound 13 was obtained following the general procedure C.
A solution of compound 10 (70 mg, 0.185) in CH2Cl2 (10 mL) and
BBr3 (2.0 eq., 0.37 mL, 0.37 mmol, 1 M in CH2Cl2) were used. The
reaction mixture was stirred for 3 h. After flash chromatography
(dichloromethane/MeOH 90/10), compound 13 was obtained as
a yellow solid (35 mg, 53%). Rf: 0.2 (dichloromethane/MeOH 90/10),
A
solution of 1-benzensulfonyl-2-(6-chloro-pyrazin-2-yl)-6-
methoxy-1H-indole 14 (500 mg, 1.25 mmol) and 4-
cyanophenylboronic acid (239 mg, 1.62 mmol) in a mixture of
toluene (7 mL), ethanol (5 mL) and aqueous saturated NaHCO3
solution (4 mL) was added. The reaction was carried out under
m
Wave irradiation for 15 min at 150 ꢁC. Flash chromatography
mp 250 ꢁC; IR (ATR Diamond, cmꢀ1
1439, 1294, 1222, 1144, 954, 830, 789, 775;1H NMR (DMSO-d6,
250 MHz)
)
n
3698, 3356, 2919, 1627, 1599,
(petroleum ether/EtOAc 70/30) yielded compound 16 as an orange
solid (424 mg, 73%). Rf: 0.2 (petroleum ether/EtOAc70/30); mp
d
3.30 (s, 3H, SO2CH3), 6.57 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.3 Hz,
142 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
2930, 2226, 1610, 1518, 1368,
H5), 6.80 (s, 1H, H3), 7.07 (s, 1H, H7), 7.36 (d, 1H, J ¼ 8.3 Hz, H4), 8.11
(dd, 4H, J ¼ 12.8 Hz, J’ ¼ 8.8 Hz, 2 ꢂ H300 þ 2 ꢂ H200), 8.53 (dd, 1H,
J ¼ J’ ¼ 2.3 Hz, H40), 8.83 (d, 1H, J ¼ 2.0 Hz, H20), 9.09 (d, 1H,
J ¼ 2.0 Hz, H60), 9.14 (s, 1H, OH), 11.40 (s, 1H, NH);13C NMR (DMSO-
1253, 1117, 1145, 1111, 848, 758, 726; 1H NMR (CDCl3, 250 MHz)
d
3.91 (s, 3H, OCH3), 6.93 (dd, 1H, J ¼ 7.5 Hz, J’ ¼ 2.5 Hz, H5), 6.97 (s,
1H, H3), 7.27e7.48 (m, 3H, Harom), 7.46 (d, 1H, J ¼ 7.5 Hz, H4), 7.58
(d, 2H, J ¼ 7.5 Hz, Harom), 7.72 (s, 1H, H7), 7.78 (d, 2H, J ¼ 7.5 Hz,
2 ꢂ H300), 8.13 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H200), 8.90 (s, 1H, H30), 9.00 (s,
d6, 100.6 MHz)
d 43.4 (CH3), 96.8 (CH), 99.4 (CH), 120.8 (Cq), 124.1
(Cq), 126.9 (2 ꢂ CH), 127.6 (2 ꢂ CH), 127.8 (2 ꢂ CH), 131.9 (CH), 133.1
(Cq), 133.9 (Cq), 138.2 (Cq), 140.1 (Cq), 140.3 (Cq), 140.5 (CH), 141.9
(CH), 154.0 (Cq); HRMS (EI-MS): m/z calculated for C20H17 N2O3S
365.0960 found 365.0977.
1H, H50);13C NMR (CDCl3, 100.6 MHz)
d 55.8 (CH3),100,4 (CH), 114,1
(CH), 116.0 (Cq), 117.2 (CH), 122.2 (CH), 116.2 (CH), 116.9 (Cq), 122.1
(CH), 123.8 (Cq), 126.7 (2 ꢂ CH), 127.5 (2 ꢂ Cq), 127.6 (2 ꢂ CH), 128.8
(2 ꢂ CH), 132.7 (2 ꢂ CH), 133.8 (CH), 136.2 (Cq), 137.2 (Cq), 139.9
(Cq), 140.3 (Cq), 145.2 (Cq); HRMS (EI-MS): m/z calculated for
C26H19 N4O3S 467.1178 found 467.1186.
7.1.18. 1-Benzensulfonyl-2-(6-chloro-pyrazin-2-yl)-6-methoxy-1H-
indole (14)
Compound 6 was obtained following the general procedure A. A
7.1.21. 1-Benzenesulfonyl-2-[6-(4-methanesulfonyl-phenyl)-pyrazin-
2-yl]-6-methoxy-1H-indole (17)
solution of compound
3
(300 mg, 0.53 mmol), 2,6-
dicholoropyrazine (83 mg, 0.55 mmol) and CuI (10 mg,
0.053 mmol) in THF (10 mL) were used. The reaction was carried
Compound 17 was obtained following the general procedure B.
solution of compound 14 (450 mg, 1.12 mmol) and 4-
A
out under
m
Wave irradiation for 20 min at 100 ꢁC. After flash
methanesulfonylphenylboronic acid (270 mg, 1.35 mmol) in
a mixture of toluene (7 mL), ethanol (5 mL) and aqueous saturated
NaHCO3 solution (4 mL) was added. The reaction was carried out
chromatography (petroleum ether/EtOAc 90/10), compound 14 was
obtained as yellow oil (211 mg, 98%). Rf: 0.25 (petroleum ether/
EtOAc 90/10); IR (ATR Diamond, cmꢀ1
)
n
1616, 1509, 1407, 1366,
under m
Wave irradiation for 15 min at 150 ꢁC. Flash chromatog-
1279, 1190, 1166, 1089, 1008, 726; 1H NMR (CDCl3, 250 MHz)
d
3.92
raphy (petroleum ether/EtOAc 50/50) afforded compound 17 as an
(s, 3H, OCH3), 6.91 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.2 Hz, H5), 6.96 (s, 1H,
H3), 7.36 (m, 3H, Harom), 7.48 (d, 1H, J ¼ 7.7 Hz, H4), 7.66 (d, 2H,
J ¼ 7.5 Hz, Harom), 7.73 (d, 1H, J ¼ 1.7 Hz, H7), 8.58 (s, 1H, H30), 8.87
orange solid (264 mg, 65%). Rf: 0.25 (petroleum ether/EtOAc 50/50),
mp 163 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
2924, 1623, 1368, 1308, 1172,
1150, 1091, 839, 776, 763, 726;1H NMR (CDCl3, 250 MHz)
d
3.31 (s,
(s, 1H, H50);13C NMR (CDCl3, 100.6 MHz)
d
55.9 (CH3), 100.4 (CH),
3H, SO2CH3), 3.88 (s, 3H, OCH3), 6.99 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.0 Hz,
H5), 7.26 (s, 1H, H3), 7.51e7.57 (m, 4H, Harom), 7.65e7.69 (m, 3H,
H4 þ H7 þ Harom), 8.11 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H300), 8.39(d, 2H,
J ¼ 8.5 Hz, 2 ꢂ H200), 9.02 (s, 1H, H30), 9.39 (s, 1H, H50);13C NMR
114.1 (CH), 114.6 (CH), 118.1(CH), 122.4 (CH), 123.8 (Cq), 127.0 (CH),
128.3 (CH), 128.9 (CH), 134.0 (CH), 134.9 (Cq), 136.7 (Cq), 140.1 (Cq),
142.6 (CH), 143.8 (CH), 146.9 (Cq), 147.8 (Cq), 159.2 (Cq); HRMS (EI-
MS): m/z calculated for C19H15 N3O3SCl 400.0523 found 400.0520.
(CDCl3, 100.6 MHz) d 43.38 (CH3), 55.6 (CH3), 99.7 (CH), 113.6 (CH),
116.8 (CH), 122.7 (CH), 123.3 (Cq), 126.4 (2 ꢂ CH), 127.6 (2 ꢂ CH),
127.8 (2 ꢂ CH), 129.5 (2 ꢂ CH),134.5 (CH), 135.7 (Cq), 136.1 (Cq),
138.8 (Cq), 140.3 (CH), 141.2 (Cq), 1341.7 (Cq), 144.6 (CH), 146.3 (Cq),
148.4 (Cq), 158.3 (Cq); HRMS (EI-MS): m/z calculated for C26H22
N3O5S2 520.1001 found 520.1002.
7.1.19. 1-Benzenesulfonyl-6-methoxy-2-[6-(4-methoxyphenyl)-
pyrazin-2-yl]-1H-indole (15)
Compound 15 was obtained following the general procedure B.
A
solution of compound 14 (500 mg, 1.25 mmol) and 4-
methoxyphenylboronic acid (285 mg, 1.87 mmol) in a mixture of
toluene (7 mL), ethanol (5 mL) and aqueous saturated NaHCO3
solution (4 mL) was added. The reaction was carried out under
7.1.22. 6-Methoxy-2-[6-(4-methoxy-phenyl)-pyrazin-2-yl]-1H-
indole (18)
m
Wave irradiation for 15 min at 150 ꢁC. Flash chromatography
Compound 18 was obtained following the general procedure D.
A solution of compound 15 (300 mg, 0.636 mmol) in THF (7 mL) and
Bu4NF (1.5 eq., 0.95 mL, 1 M in THF, 0.95 mmol) were used. The
reaction was refluxed for 15 h. Flash chromatography (CH2Cl2/
MeOH 90/10) afforded compound 18 as a yellow solid (187 mg,
88%). Rf: 0.25 (petroleum ether/EtOAc 60/40); mp 140 ꢁC; IR (ATR
(petroleum ether/EtOAc 60/40) yielded compound 15 as an orange
solid (424 mg, 72%). Rf: 0.25 (petroleum ether/EtOAc 60/40); mp
138 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
2361, 1607, 1513, 1361, 1280, 1249,
1169, 1029, 830, 808, 725; 1H NMR (CDCl3, 250 MHz)
d
3.89 (s, 3H,
OCH3), 3.92 (s, 3H, OCH3), 6.90 (s, 1H, H3), 6.93 (d, 1H, J ¼ 8.8 Hz,
H4), 7.03 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H300), 7.32e7.38 (m, 3H, Harom), 7.47
(d, 1H, J ¼ 4.7 Hz, H5), 7.67 (d, 2H, J ¼ 7.2 Hz, Harom), 7.76 (s, 1H,
H7), 7.98 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H200), 8.75 (s, 1H, H30), 8.95 (s, 1H,
Diamond, cmꢀ1
1170; 1023; 833. 1H NMR (CDCl3, 250 MHz)
3.91 (s, 3H, OCH3), 6.83 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.3 Hz, H5), 6.95 (s,
)
n
3245; 2332; 1606; 1542; 1510; 1438; 1306; 1251;
3.89 (s, 3H, OCH3),
d

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5427
1H, H3), 7.06 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 7.05 (s,1H, H7), 7.56 (d, 1H,
7.1.26. 4-[5-(6-Hydroxy-1H-indol-2-yl)-pyrazin-2-yl]-benzonitrile
(22)
J ¼ 8.8 Hz, H4), 8.85 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 8.75 (s, 1H, H30),
8.89 (s,1H, H50), 9.36 (s,1H, NH). 13C NMR (CDCl3,100.6 MHz)
d
55.4
Compound 22 was obtained following the general procedure B
C. A solution of compound 19 (200 mg, 0.612 mmol) in CH2Cl2
(10 mL) and BBr3 (5.0 eq., 3.06 mL, 3.06 mmol, 1 M in CH2Cl2) were
used. The reaction mixture was stirred for 5 h. After flash chro-
matography (petroleum ether/EtOAc 50/50), compound 22 was
obtained as a green solid (120 mg, 63%). Rf: 0.2 (ꢀp1etroleum ether/
(CH3), 55.6 (CH3), 94.2 (CH), 102.2 (CH), 111.2(CH), 114.4 (2 ꢂ CH),
122.3 (CH), 123.4 (Cq), 128.3 (2 ꢂ CH), 128.9 (Cq), 132.9 (Cq), 137.7
(Cq), 138.2 (CH), 138.7 (CH), 145.2 (Cq), 150.9 (Cq), 157.8 (Cq), 161.2
(Cq). HRMS (EI-MS): m/z calculated for C20H18 N3O2 332.1399
found 332.1404.
EtOAc 50/50); mp 241 ꢁC; IR (ATR Diamond, cm
) n 3718, 3368,
7.1.23. 4-[6-(6-Methoxy-1H-indol-2-yl)-pyrazin-2-yl]-benzonitrile
(19)
2230, 1626, 1543, 1517, 1442, 1246, 1217, 1186, 1146, 1112, 817, 739,
693, 678;1H NMR (DMSO-d6, 250 MHz)
d
6.61 (dd, 1H, J ¼ 7.2 Hz,
Compound 19 was obtained following the general procedure D.
A solution of compound 16 (400 mg, 0.85 mmol) in THF (7 mL) and
Bu4NF (1.5 eq., 1.27 mL, 1 M in THF, 1.27 mmol) were used. The
reaction was refluxed for 15 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 19 as a yellow solid
(244 mg, 88%). Rf: 0.18 (petroleum ether/EtOAc 60/40); mp 200 ꢁC;
J’ ¼ 1.7 Hz, H5), 6.91 (s, 1H, H3), 7.31 (s,1H, H7), 7.40 (d, 1H,
J ¼ 4.2 Hz, H4), 8.06 (d, 2H, J ¼ 7.0 Hz, 2 ꢂ H300), 8.62 (d, 2H,
J ¼ 7.0 Hz, 2 ꢂ H200), 9.91 (s, 1H, H30), 9.20 (s, 1H, H50), 9.23 (s, 1H,
OH), 11.51 (s, 1H, NH);13C NMR (DMSO-d6, 100.6 MHz)
d 96.5 (CH),
103.2 (CH), 111.2 (CH) 112.2 (Cq), 118.7 (Cq), 121.7 (CH), 121.8 (Cq),
127.5 (2 ꢂ CH), 132.1 (Cq), 132.7 (2 ꢂ CH), 138.6 (CH), 139.1 (Cq),
140.1 (Cq), 140.9 (CH), 145.8 (Cq), 147.8 (Cq), 154.9 (Cq). HRMS (EI-
MS): m/z calculated for C19H13 N4O 313.1089 found 313.1102.
IR (ATR Diamond, cmꢀ1
1254, 1192, 1163, 1112, 1013, 819;1H NMR (CDCl3, 250 MHz)
)
n
3408, 2924, 2230, 1628, 1524, 1511, 1448,
3.89
d
(s, 3H, OCH3), 6.84 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.0 Hz, H5), 6.95 (s, 1H,
H3), 7.17 (d, 1H, J ¼ 1.2 Hz, H7), 7.57 (d, 1H, J ¼ 8.8 Hz, H4), 7.85 (d,
2H, J ¼ 8.5 Hz, 2 ꢂ H300), 8.22 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H200), 8.82 (s, 1H,
H30), 9.03 (s, 1H, H50), 9.30 (s, 1H, NH);13C NMR (CDCl3, 100.6 MHz)
7.1.27. 2-[6-(4-Methanesulfonyl-phenyl)-pyrazin-2-yl]-1H-indol-6-ol
(23)
Compound 23 was obtained following the general procedure C.
A solution of compound 20 (150 mg, 0.41 mmol) in CH2Cl2 (10 mL)
and BBr3 (5.0 eq., 2.05 mL, 2.05 mmol 1 M in CH2Cl2) were used.
The reaction mixture was stirred for 5 h. After flash chromatog-
raphy (CH2Cl2/MeOH 90/10), compound 23 was obtained as a red
solid (62 mg, 42%). Rf: 0.12 (CH2Cl2/MeOH 90/10); mp >250 ꢁC; IR
d
55.8 (CH3), 94.1 (CH), 103.3 (CH), 111.6 (CH), 118.9 (Cq), 120.5 (Cq),
122.5 (CH), 127.5 (2 ꢂ CH), 132.7 (2 ꢂ CH), 138.0 (Cq), 138.5 (Cq),
138.8(Cq), 139.3 (CH), 140.6 (Cq), 140.9 (CH), 142.8 (Cq), 150.2 (Cq),
154.4 (Cq); HRMS (EI-MS): m/z calculated for C20H15 N4O 327.1246
found 327.1239.
(ATR Diamond, cmꢀ1
1H NMR (DMSO-d6, 250 MHz)
)
n
3947, 3743, 3559, 2911,1146,1062, 829, 700;
3.29 (s, 3H, SO2CH3), 6.61 (dd, 1H,
7.1.24. 2-[6-(4-Methanesulfonyl-phenyl)-pyrazin-2-yl]-6-methoxy-
1H-indole (20)
d
J ¼ 5.5 Hz, J’ ¼ 1.3 Hz, H5), 6.91 (s, 1H, H3), 7.32 (s, 1H, H7), 7.42 (d,
1H, J ¼ 5.2 Hz, H4), 8.11 (d, 2H, J ¼ 5.2 Hz, 2 ꢂ H300), 8.66 (d, 2H,
J ¼ 5.2 Hz, 2 ꢂ H200), 9.15 (s, 1H, H30), 9.21 (s, 1H, H50), 9.23 (s, 1H,
Compound 20 was obtained following the general procedure D.
A solution of compound 17 (460 mg, 0.88 mmol) in THF (15 mL) and
Bu4NF (1.5 eq., 1.32 mL, 1 M in THF, 1.32 mmol) were used. The
reaction was refluxed for 15 h. Flash chromatography (CH2Cl2/
MeOH 90/10) afforded compound 20 as a yellow solid (330 mg,
99%), Rf: 0.2 (petroleum ether/EtOAc 50/50); mp 246 ꢁC; IR (ATR
OH), 11.50 (s, 1H, NH);13C NMR (CDCl3, 100.6 MHz)
d 43.4 (CH3),
96.5 (CH), 103.3 (CH), 111.2 (CH) 121.7 (CH), 121.8 (Cq), 127.4
(2 ꢂ CH), 127.7 (2 ꢂ CH), 132.1 (Cq), 138.6 (CH), 139.1 (Cq), 140.5
(Cq), 140.8 (CH), 141.6 (Cq), 145.8 (Cq), 148.1 (Cq), 154.9 (Cq); HRMS
(EI-MS): m/z calculated for C19H16 N3O3S 366.0912 found
366.0926.
Diamond, cmꢀ1
839, 826, 813, 711;1H NMR (CDCl3, 250 MHz)
)
n
3587, 3005, 1586, 1512, 1305, 1249, 1173, 1148,
3.28 (s, 3H,
d
SO2CH3), 3.82 (s, 3H, OCH3), 6.74 (dd,1H, J ¼ 8.8 Hz, J’ ¼ 2.3 Hz, H5),
7.02 (s, 1H, H3), 7.37 (s, 1H, H7), 7.52 (d, 1H, J ¼ 10 Hz, H4), 8.12 (d,
2H, J ¼ 8.5 Hz, 2 ꢂ H300), 8.67 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H200), 9.18 (s, 1H,
H30), 9.25 (s, 1H, H50), 11.69 (s, 1H, NH);13C NMR (CDCl3, 100.6 MHz)
7.1.28. 1-Benzenesulfonyl-5-benzyloxy-2-(5-chloro-pyrazin-3-yl)-
1H-indole (26)
Compound 26 was obtained following the general procedure A.
d
43.4 (CH3), 55.1 (CH3), 94.4 (CH),103.1 (CH),110.8 (Cq),121.9 (CH),
A
solution of compound 24 (500 g, 0.76 mmol), 2,6-
122.6 (Cq), 127.4 (2 ꢂ CH), 127.8 (2 ꢂ CH), 132.8 (Cq), 138.7 (Cq),
138.9(CH), 140.5 (Cq), 141.0 (CH), 141.7 (Cq), 145.7 (Cq), 148.2 (Cq),
157.0 (Cq).
dichloropyrazine (125.5 mg, 0.84 mmol) and CuI (14.6 mg,
0.076 mmol) in THF (15 mL) were used. The reaction was realized
under m
Wave irradiation for 20 min at 100 ꢁC. After flash chroma-
tography (petroleum ether/EtOAc 80/20), compound 26 was ob-
7.1.25. 2-[6-(4-Hydroxy-phenyl)-pyrazin-2-yl]-1H-indol-6-ol (21)
Compound 21 was obtained following the general procedure C.
A solution of compound 18 (150 mg, 0.452 mmol) in CH2Cl2 (7 mL)
and BBr3 (3.0 eq,1.35 mL,1.35 mmol,1 M in CH2Cl2) were used. The
reaction mixture was stirred for 10 h. Flash chromatography
(CH2Cl2) afforded compound 21 as a brown solid (101 mg, 73%). Rf:
tained as yellow oil (3.02 g, 83%). Rf: 0.25 (petroleum ether/EtOAc
80/20); IR (ATR Diamond, cmꢀ1
)
n
3616, 2923, 2348, 1578, 1513,
1449, 1372, 1221, 1177, 1153, 1089, 1007, 881, 754, 726, 684;1H NMR
(CDCl3, 250 MHz) 5.10 (s, 2H, OCH2), 6.95 (s, 1H, H3), 7.01 (d, 1H,
d
J ¼ 2.5 Hz, H4), 7.12 (dd,1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.33e7.50 (m,
8H, Harom), 7.60e7.64 (m, 2H, Harom), 8.11 (d, 1H, J ¼ 9.0 Hz, H7),
0.4 (CH2Cl2/MeOH 96/04); mp >250 ꢁC; IR (ATR Diamond, cmꢀ1
3637, 3576, 3394, 2956, 1593, 1511, 1417, 1400, 1266, 1204, 1175,
)
n
8.60 (s,1H, H30), 8.88 (s,1H, H50);13C NMR (CDCl3,100.6 MHz)
d 70.5
(CH2), 105.1 (CH), 116.2 (CH), 117.3 (CH), 118.0 (CH), 127.0 (2 ꢂ CH),
127.5 (2 ꢂ CH), 128.0 (Cq), 128.6 (2 ꢂ CH), 128.8 (2 ꢂ CH), 131.0
(Cq),133.2 (Cq), 133.8 (CH), 136.5 (Cq), 136.6 (Cq), 136.8 (Cq), 143.0
(CH), 143.9 (CH), 146.6 (Cq), 147.9 (Cq), 156.4 (Cq); HRMS (EI-MS) m/
z calculated for C25H18ClN3O3S 476.0836 found 476.0854.
1116, 807;1H NMR (DMSO-d6, 250 MHz)
d
6.59 (dd, 1H, J ¼ 8.5 Hz,
J’ ¼ 2.2 Hz, H5), 6.89e6.95 (m, 3H, H3, 2 ꢂ H300), 7.22 (s,1H, H7), 7.39
(d, 1H, J ¼ 8.5 Hz, H4), 8.25 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 8.91 (s, 1H,
H30), 8.99 (s, 1H, H50), 9.22 (s, 1H, OH), 9.91 (s, 1H, OH), 11.35 (s, 1H,
NH);13C NMR (CDCl3, 100.6 MHz)
d 96.5 (CH), 99.8 (CH), 110.9 (CH)
115.5 (2 ꢂ CH), 121.4 (Cq), 126.9 (CH), 127.2 (Cq), 128.4 (2 ꢂ CH),
137.4 (Cq), 138.2 (Cq), 138.8 (Cq), 145.2 (Cq), 154.4 (2 ꢂ CH), 154.5
(Cq), 159.3 (Cq). HRMS (EI-MS): m/z calculated for C18H14 N3O2
304.1086 found 304.1082.
7.1.29. 4-[5-(1-Benzenesulfonyl-5-benzyloxy-1H-indol-2-yl)-pyridin-
3-yl]-benzonitrile (27)
Compound 27 was obtained following the general procedure B.
Compound 25 (250 mg, 0.48 mmol) and 4-cyanophenylboronic

5428
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
acid (85 mg, 0.58 mmol) in a mixture of toluene (22 mL), ethanol
(11 mL) and aqueous saturated NaHCO3 solution (7 mL) were used.
The reaction was refluxed for 4 h. Flash chromatography (petro-
leum ether/EtOAc 70/30) afforded compound 27 as a yellow solid
(198 mg, 76%). Rf: 0.1 (petroleum ether/EtOAc 60/40); mp 195 ꢁC; IR
156.3 (CH), 161.2 (Cq); HRMS (EI-MS) m/z calculated for C32H26
N3O4S 548.1644 found 548.1642.
7.1.32. 4-[6-(1-Benzenesulfonyl-5-benzyloxy-1H-indol-2-yl)-pyrazin-
2-yl]-benzonitrile (30)
Compound 30 was obtained following the general procedure B.
A solution of compound 26 (500 mg, 1.05 mmol) and 4-
(ATR Diamond, cmꢀ1
1145, 1089, 840, 743, 724, 685;1H NMR (CDCl3, 250 MHz)
)
n
2230, 1608, 1474, 1447, 1369, 1203, 1170,
5.09 (s,
d
2H,OCH2), 6.64 (s, 1H, H3), 7.00 (d, 1H, J ¼ 2.5 Hz, H4), 7.11 (dd, 1H,
J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.25e7.43 (m,10H, Harom), 7.81 (br s, 4H,
2 ꢂ H200 þ 2 ꢂ H300), 8.18 (t, 1H, J ¼ 2.5 Hz, H40), 8.23 (d, 1H,
J ¼ 10.0 Hz, H7), 8.63 (d, 1H, J ¼ 2.5 Hz, H20), 8.89 (d, 1H, J ¼ 2.5 Hz,
cyanophenylboronic acid (231 mg, 1.57 mmol) in a mixture of
toluene (3.3 mL), ethanol (2.1 mL) and aqueous saturated NaHCO3
solution (1.8 mL) was used. The reaction mixture was carried out
under m
Wave irradiation for 30 min at 150 ꢁC. Flash chromatog-
H60);13C NMR (CDCl3, 100.6 MHz)
d
70.5 (CH2), 104.7 (CH), 115.3
raphy (petroleum ether/EtOAc 70/30) yielded compound 30 as
(2 ꢂ CH), 117.7 (CH), 118.6 (Cq), 126.5 (2 ꢂ CH), 127.5 (3 ꢂ CH), 128.0
(2 ꢂ CH), 128.6 (2 ꢂ CH), 128.9 (2 ꢂ CH), 130.8 (Cq), 131.3 (Cq), 132.9
(2 ꢂ CH), 133.0 (Cq), 133.5 (Cq), 133.9 (CH), 136.8 (Cq), 136.9 (Cq),
137.2 (CH), 138.4 (Cq), 141.9 (Cq), 147.9 (Cq), 148.0 (CH), 148.7 (CH),
156.6 (Cq); HRMS (EI-MS): m/z calculated for C33H24 N3O3S
542.1538 found 542.1556.
a yellow solid (512 mg, 90%). Rf: 0.25ꢀ(p1 etroleum ether/EtOAc 70/
1364, 1219, 1153, 1088, 1064, 1012, 863, 814, 811, 747, 725, 702;1H
30); mp 217 ꢁC; IR (ATR Diamond, cm
) n 2226, 1605, 1523, 1451,
NMR (CDCl3, 250 MHz) 5.11 (s, 2H, OCH2), 6.98 (s, 1H, H3), 7.06 (d,
d
1H, J ¼ 2.5 Hz, H4), 7.15 (dd,1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.30e7.61
(m, 10 H, Harom), 7.85 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H300), 8.15 (d, 1H,
J ¼ 9.0 Hz, H7), 8.20 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H200), 8.97 (s, 1H, H30),
7.1.30. 1-Benzenesulfonyl-5-benzyloxy-2-[5-(4-methanesulfonyl-
phenyl)-pyridin-3-yl]-1H-indole (28)
9.05 (s, 1H, H50);13C NMR (CDCl3, 100.6 MHz)
d 70.5 (CH2), 105.2
(CH), 113.5 (Cq), 116.0 (CH), 117.2 (CH), 117.3 (CH), 118.0 (Cq), 118.5
(Cq),126.8 (2 ꢂ CH),127.5 (2 ꢂ CH),127.6 (2 ꢂ CH); 128.1 (CH),128.6
(2 ꢂ CH), 128.8 (2 ꢂ CH), 131.1 (Cq), 132.8 (CH), 133.2 (Cq), 133.8
(2 ꢂ CH), 136.7 (Cq), 137.0 (Cq), 138.2 (Cq), 140.4 (Cq), 140.7 (CH),
145.4 (CH), 146.9 (Cq), 149.0 (Cq); HRMS (EI-MS): m/z calculated for
C32H23 N4O3S 543.2643 found 543.2645.
Compound 28 was obtained following the general procedure B.
Compound
25
(500
mg,
0.96
mmol)
and
4-
methylsulfonylphenylboronic acid (231 mg, 1.15 mmol) in
a mixture of toluene (44 mL), ethanol (22 mL) and aqueous satu-
rated NaHCO3 solution (14 mL) were used. The reaction was
refluxed for 8 h. Flash chromatography (petroleum ether/EtOAc 40/
60) afforded compound 28 as a yellow solid (198 mg, 96%). Rf: 0.25
(petroleum ether/EtOAc 40/60); mp 147 ꢁC; IR (ATR Diamond,
7.1.33. 1-Benzenesulfonyl-5-benzyloxy-2-[6-(4-methanesulfonyl-
phenyl)-pyrazin-2-yl]-1H-indole (31)
Compound 31 was obtained following the general procedure B.
A solution of compound 26 (620 mg, 1.30 mmol) and 4-
cmꢀ1
250 MHz)
)
n
3050, 1431, 1371, 1145, 799, 743;1H NMR (DMSO-d6,
3.29 (s, 3H, SO2CH3), 5.11 (s, 2H,OCH2), 7.07 (s, 1H, H3),
d
7.12 (dd, 1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.18 (d, 1H, J ¼ 10.0 Hz, H7),
7.33e7.49 (m, 10H, Harom), 8.04 (s, 1H, H4), 8.09 (d, 2H, J ¼ 8.5 Hz,
2 ꢂ H300), 8.12 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H200), 8.35 (t,1H, J ¼ 2.5 Hz, H40),
8.79 (d, 1H, J ¼ 2.5 Hz, H20), 9.05 (d, 1H, J ¼ 2.5 Hz, H60);13C NMR
methylsulfonylphenylboronic acid (390 mg, 1.95 mmol) in
a mixture of toluene (3.3 mL), ethanol (2.1 mL) and aqueous satu-
rated NaHCO3 solution (1.8 mL) was used. The reaction was carried
out under m
Wave irradiation for 30 min at 150 ꢁC. Flash chroma-
(DMSO-d6, 100.6 MHz)
d
59.3 (CH3), 83.3 (CH2), 126.1 (2 ꢂ CH),
tography (petroleum ether/EtOAc 50/50) yielded compound 31 as
127.6 (4 ꢂ CH), 127.7 (2 ꢂ CH), 128.0 (Cq), 128.1 (Cq), 128.2 (Cq),
128.4 (4 ꢂ CH),128.5 (Cq),128.6 (3 ꢂ CH),128.7 (3 ꢂ CH),128.8 (Cq),
129.3 (CH), 131.3 (CH), 131.4 (CH), 131.9 (Cq), 132.6 (Cq), 132.8 (Cq),
155.9 (2 ꢂ Cq); HRMS (EI-MS): m/z calculated for C33H27 N2O5S2
595.1361 found 595.1342.
a yellow solid (635 mg, 82%). Rf: 0.25 ꢀ(p1etroleum ether/EtOAc 50/
50); mp 186 ꢁC; IR (ATR Diamond, cm
) n 1601, 1507, 1446, 1369,
1253, 1218, 1185, 1167, 1149, 1088, 1012, 844, 811, 753, 722, 699,
682;1H NMR (CDCl3, 250 MHz)
d
3.12 (s, 3H, SO2CH3), 5.07 (s, 2H,
OCH2), 6.96 (s, 1H, H3), 7.07 (d, 1H, J ¼ 2.2 Hz, H4), 7.11 (dd, 1H,
J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.30e7.70 (m, 10H, Harom), 8.07e8.13
(m, 3H, 2 ꢂ H300 þ H7), 8.25 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 8.26 (s, 1H,
7.1.31. 1-Benzenesulfonyl-5-benzyloxy-2-[6-(4-methoxy-phenyl)-
pyrazin-2-yl]-1H-indole (29)
H30), 9.02 (s, 1H, H50);13C NMR (CDCl3, 100.6 MHz)
d 44.5 (CH3),
Compound 29 was obtained following the general procedure
B. A solution of compound 26 (500 mg, 1.05 mmol) and 4-
methoxyphenylboronic acid (192 mg, 1.26 mmol) in a mixture
of toluene (3.3 mL), ethanol (2.1 mL) and aqueous saturated
NaHCO3 solution (1.8 mL) was used The reaction was carried out
70.5 (CH2), 105.1 (CH), 112.3 (Cq), 115.9 (CH), 117.2 (CH), 117.3 (CH),
126.8 (2 ꢂ CH),127.4 (2 ꢂ CH),127.5 (CH),127.9 (CH),128.0 (2 ꢂ CH),
128.5 (CH), 128.6 (2 ꢂ CH), 128.8 (2 ꢂ CH), 131.1 (Cq), 133.1 (Cq),
133.8. (CH), 136.7 (2 ꢂ Cq), 136.9 (Cq), 138.1 (Cq), 140.7 (CH), 141.3
(Cq), 141.5 (Cq), 145.5 (CH), 156.4 (Cq); HRMS (EI-MS): m/z calcu-
lated for C32H26 N3O5S2 596.1314 found 596.1306.
under
m
Wave irradiation for 30 min at 150 ꢁC. Flash chroma-
tography (petroleum ether/EtOAc 70/30) yielded compound 29
as a yellow solid (447 mg, 78%). Rf: 0.45 (petroleum ether/EtOAc
7.1.34. 4-[5-(5-Benzyloxy-1H-indol-2-yl)-pyridin-3-yl]-benzonitri-
le (32)
60/40); mp 136 ꢁC; IR (ATR Diamond, cmꢀ1
) n 3068, 1031, 1608,
1513, 1449, 1418, 1369, 1303, 1253, 1219, 1185, 1167, 1149, 1122,
Compound 32 was obtained following the general procedure D.
A solution of compound 27 (130 mg, 0.24 mmol) in THF (4 mL) and
1.5 eq of Bu4NF (0.36 mL, 1 M in THF, 0.36 mmol) were used. The
reaction was refluxed for 4 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 32 as a yellow solid (70 mg,
73%). Rf: 0.34 (petroleum ether/EtOAc 40/60); mp 93 ꢁC; IR (ATR
1087, 1070, 1014, 845, 813, 753, 722, 700;1H NMR (CDCl3,
250 MHz)
d 3.90 (s, 3H, OCH3), 5.08 (s, 2H, OCH2), 6.90 (s, 1H,
H3), 7.07 (m, 2H, Harom), 7.50 (s, 1H, H4), 7.10 (dd, 1H,
J ¼ 5.8 Hz, J’ ¼ 1.8 Hz, H6), 7.27e7.47 (m, 8H, Harom), 7.64 (d, 2H,
J ¼ 8.8 Hz, 2 ꢂ H300), 8.0 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 8.12 (d, 1H,
J ¼ 9.0 Hz, H7), 8.77 (s, 1H, H30), 8.98 (s, 1H, H50);13C NMR
Diamond, cmꢀ1
835, 790;1H NMR (CDCl3, 250 MHz)
d
)
n
2226, 1587, 1456, 1386, 1295, 1212, 1160, 1023,
5.30 (s, 2H, OCH2), 6.89 (s,1H,
(CDCl3, 100.6 MHz)
d
55.4 (CH3), 70.5 (CH2), 105.1 (CH), 114.4
(2 ꢂ CH), 115.5 (CH), 116.3 (CH), 117.2 (CH), 127.0 (2 ꢂ CH), 127.5
(2 ꢂ CH), 128.0 (CH), 128.5 (2 ꢂ CH), 128.6 (2 ꢂ CH); 128.8
(2 ꢂ CH), 131.2 (Cq), 133.0 (Cq), 133.6 (CH), 136.8 (2 ꢂ Cq), 137.2
(Cq), 138.8 (Cq), 140.1 (CH), 143.3 (CH), 146.3 (Cq), 150.9 (Cq),
H3), 7.00 (dd, 1H, J ¼ 9.0 Hz, J ¼ 2.5 Hz, H6), 7.18 (d, 1H, J ¼ 2.0 Hz,
H4), 7.33e7.50 (m, 5H, Harom), 7.75 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H300), 7.82
(d, 2H, J ¼ 8.5 Hz, 2 ꢂ H200), 8.07 (dd, 1H, J ¼ J’ ¼ 2.0 Hz, H40), 8.43 (d,
1H, J ¼ 10 Hz, H7), 8.75 (s, 1H, H20), 8.83 (s, 1H, H60), 11.2 (s, 1H,

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5429
NH);13C NMR (CDCl3, 100.6 MHz)
d
70.9 (CH2), 101.9 (CH), 103.9
NH);13C NMR (CDCl3, 100.6 MHz)
d
70.8 (CH2), 102.8 (CH), 104.1
(CH), 106.2 (Cq), 111.9(CH), 114.6 (CH), 118.5 (Cq), 127.5 (3 ꢂ CH),
127.8 (2 ꢂ CH), 128.0 (2 ꢂ CH), 128.5 (2 ꢂ CH),129.4 (Cq), 130.6 (Cq),
132.6 (Cq), 132.7 (Cq), 133.0 (2 ꢂ CH), 137.5 (2 ꢂ Cq), 154.0 (2 ꢂ Cq),
155.0 (Cq); HRMS (EI-MS): m/z calculated for C27H20 N3O
402.1626 found 402.1606.
(CH), 112.3 (CH), 116.1 (CH), 127.5 (2 ꢂ CH), 127.6 (2 ꢂ CH), 127.9
(2 ꢂ CH), 128.1 (Cq), 128.6 (2 ꢂ CH), 129.1 (Cq), 129.4 (Cq), 132.5
(Cq), 132.8 (2 ꢂ CH), 133.7 (Cq), 137.4 (Cq), 139.3 (Cq), 140.5 (Cq),
141.2 (CH), 142.1 (Cq), 154.0 (Cq); HRMS (EI-MS): m/z calculated for
C26H19 N4O 403.1559 found 403.1545.
7.1.35. 5-Benzyloxy-2-[5-(4-methanesulfonyl-phenyl)-pyridin-3-
yl]-1H-indole (33)
7.1.38. 5-Benzyloxy-2-[6-(4-methansulfonyl-phenyl)-pyrazin-2-yl]-
1H-indole (36)
Compound 33 was obtained following the general procedure D
D. A solution of compound 28 (300 mg, 0.50 mmol) in THF (10 mL)
and 1.5 eq of Bu4NF (0.75 mL, 1 M in THF, 0.75 mmol) were used.
The reaction mixture was refluxed for 4 h. Flash chromatography
(petroleum ether/EtOAc 40/60) afforded compound 33 as a white
solid (229 mg, quant). Rf: 0.ꢀ21(petroleum ether/EtOAc 40/60); mp
Compound 36 was obtained following the general procedure D.
A solution of compound 31 (480 mg, 0.80 mmol) in THF (15 mL) and
3.0 eq. of Bu4NF (2.4 mL, 1 M in THF, 2.4 mmol) were used. The
reaction was refluxed for 10 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 36 as a yellow solid
(340 mg, 94%). Rf: 0.25 (petroleum ether/EtOAc 50/50); mp 245 ꢁC;
211 ꢁC; IR (ATR Diamond, cm
)
n
3349,1734,1589,1460,1303,1211,
3.30 (s, 3H,
IR (ATR Diamond, cmꢀ1
1167, 1145, 1122, 1105, 1089, 1009, 962, 834, 777, 764, 744, 731,
694;1H NMR (DMSO-d6, 250 MHz)
3.32 (s, 3H, SO2CH3), 5.13 (s,
) n 3358, 1540, 1446, 1294, 1231, 1217, 1187,
1145, 1089, 956, 759;1H NMR (DMSO-d6, 250 MHz)
d
SO2CH3), 5.12 (s, 2H, OCH2), 6.89 (dd,1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6),
7.10 (s, 1H, H3), 7.15 (d, 1H, J ¼ 2.5 Hz, H4), 7.32e7.65 (m, 6H,
Harom þ H7), 8.09 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 8.14 (d, 2H,
J ¼ 8.5 Hz, 2 ꢂ H200), 8.57 (dd, 1H, J ¼ J’ ¼ 2.0 Hz, H40), 8.88 (d, 1H,
J ¼ 1.75 Hz, H20), 9.14 (d, 1H, J ¼ 1.75 Hz, H60), 11.63 (s, 1H, NH);13C
d
2H, OCH2), 6.96 (dd, 1H, J ¼ 10.0 Hz, J’ ¼ 2.5 Hz, H6), 7.21 (d, 1H,
J ¼ 2.5 Hz, H4), 7.32e7.44 (m, 6H, Harom þ H3), 7.50 (d, 1H,
J ¼ 7.5 Hz, H7), 8.12 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H300), 8.67 (d, 2H,
J ¼ 7.5 Hz, 2 ꢂ H200), 9.22 (s, 1H, H30), 9.28 (s, 1H, H50), 11.76 (s, 1H,
NMR (DMSO-d6, 100.6 MHz)
d
43.4 (CH3), 69.6 (CH2), 100.2 (CH),
NH);13C NMR (DMSO-d6,100.6 MHz)
d 43.4 (CH3), 69.6 (CH2),102.5
103.2 (CH), 112.0 (CH), 113.3 (CH), 127.5 (2 ꢂ CH), 127.6 (CH), 127.8
(2 ꢂ CH), 128.2 (CH), 128.6 (CH), 128.7 (CH), 129.9 (CH), 131.3 (CH),
131.4 (Cq), 131.9 (Cq), 132.6 (Cq), 133.9 (Cq), 134.5 (Cq) 137.6 (Cq),
140.4 (Cq), 141.8 (Cq), 146.0 (CH), 146.1 (CH), 152.7 (Cq); HRMS (EI-
MS): m/z calculated for C27H23 N2O3S 455.1429 found 455.1428.
(CH), 103.4 (CH), 112.9 (CH), 114.8 (CH), 127.4 (CH), 127.6 (3 ꢂ CH),
127.8 (2 ꢂ CH), 128.3 (3 ꢂ CH), 128.6 (Cq), 133.1 (Cq), 134.3 (Cq),
137.6 (Cq), 139.5 (CH), 140.4 (Cq), 141.2 (CH), 141.7 (Cq), 145.5 (Cq)
148.3 (Cq), 152.9 (Cq); HRMS (EI-MS): m/z calculated for C26H22
N3O3S 456.1382 found 456.1396.
7.1.36. 5-Benzyloxy-2-[6-(4-methoxy-phenyl)-pyrazin-2-yl]-1H-
indole (34)
7.1.39. 4-[5-(5-Hydroxy-1H-indol-2-yl)-pyridin-3-yl]-benzonitrile
(37)
Compound 34 was obtained following the general procedure D.
A solution of compound 29 (350 mg, 0.64 mmol) in THF (10 mL)
and 3.0 eq. of Bu4NF (1.92 mL, 1 M in THF, 1.92 mmol) were used.
The reaction was refluxed for 6 h. Flash chromatography (petro-
leum ether/EtOAc 60/40) afforded compound 34 as a yellow solid
(250 mg, 96%). Rf: 0.25 (petroleum ether/EtOAc 60/40); mp 176 ꢁC;
Compound 37 was obtained following the general procedure C. A
solution of compound 32 (50 mg, 0.12 mmol) in CH2Cl2 (5 mL) and
1.1 eq. of BBr3 (0.13 mL, 0.13 mmol, 1 M in CH2Cl2) were used. The
reaction mixture was stirred for 4 h. After flash chromatography
(petroleum ether/EtOAc 50/50), compound 37 was obtained as
a yellow solid (27 mg, 71%). Rf: 0.12 (petroleum ether/EtOAc 60/40);
IR (ATR Diamond, cmꢀ1
1153, 1088, 1012, 840, 810, 746, 724, 681;1H NMR (CDCl3,
250 MHz) 3.90 (s, 3H, OCH3), 5.13 (s, 2H, OCH2), 7.03 (dd, 1H,
)
n
3243, 2230, 1654, 1605, 1450, 1364, 1218,
mp 251 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
3268, 2915, 2226, 1585, 1432,
6.68
1214, 1161, 1134, 1046, 840, 791;1H NMR (DMSO-d6, 250 MHz)
d
d
(dd,1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 6.87 (d, 1H, J ¼ 2.5 Hz, H4), 7.01 (s,
1H, H3), 7.24 (d,1H, J ¼ 10.0 Hz, H7), 8.04 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H300),
8.09 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H200), 8.55 (d, 1H, J ¼ 2.5 Hz, H40), 8.78 (s,
1H, OH), 8.86 (d,1H, J ¼ 2.5 Hz, H20), 9.11 (d,1H, J ¼ 2.5 Hz, H60),11.47
J ¼ 9.0 Hz, J ¼ 2.3 Hz, H6), 7.06 (s, 1H, H3), 7.09 (d, 2H, J ¼ 8.8 Hz,
2 ꢂ H300), 7.20 (d, 1H, J ¼ 2.3 Hz, H4), 7.33e7.44 (m, 4H, Harom),
7.50 (d, 2H, J ¼ 6.8 Hz, Harom þ H7), 8.07 (d, 2H, J ¼ 8.8 Hz,
2 ꢂ H200), 8.79 (s, 1H, H30), 8.91 (s, 1H, H50), 9.37 (s, 1H, NH);13C
(s, 1H, NH);13C NMR (DMSO-d6, 100.6 MHz)
d 88.3 (CH), 92.32 (CH),
NMR (CDCl3, 100.6 MHz)
d
55.4 (CH3), 70.8 (CH2), 101.8 (CH), 104.1
98.3 (CH), 99.4 (Cq), 109.7 (CH), 110.8 (Cq), 115.1 (Cq), 126.9 (Cq),
127.8 (2 ꢂ CH),130.0 (CH),131.4 (Cq),132.9 (2 ꢂ CH),140.2 (Cq),144.0
(Cq), 145.4 (2 ꢂ CH), 150.5 (Cq), 154.4 (Cq); HRMS (EI-MS): m/z
calculated for C20H13 N3O 312.1137 found 312.1148.
(CH), 112.2 (CH), 114.4 (2 ꢂ CH), 115.4 (CH), 127.5 (2 ꢂ CH), 127.8
(CH), 128.4 (2 ꢂ CH), 128.5 (2 ꢂ CH), 128.8 (Cq), 129.4 (Cq), 132.3
(Cq), 134.5 (2 ꢂ Cq), 137.5 (Cq), 138.8 (CH), 139.0 (CH), 151.1 (Cq),
153.8 (Cq), 161.3 (Cq); HRMS (EI-MS) m/z calculated for C26H22
N3O2 408.1712 found 408.1728.
7.1.40. 2-[5-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-1H-indol-5-
ol (38)
7.1.37. 4-[6-(5-Benzyloxy-1H-indol-2-yl)-pyrazin-2-yl]-benzonitri-
le (35)
Compound 6 was obtained following the general procedure C C.
A solution of compound 33 (200 mg, 0.44 mmol) in CH2Cl2 (15 mL)
and 1.5 eq. of BBr3 (0.66 mL, 0.66 mmol, 1 M in CH2Cl2) were used.
The reaction mixture was stirred for 6 h. After flash chromatog-
raphy (dichloromethane), compound 38 was obtained as a pale
brown solid (93 mg, 58%). Rf: 0.17 (CH2Cl2); mp 195 ꢁC; IR (ATR
Compound 35 was obtained following the general procedure D.
A solution of compound 30 (286 mg, 0.52 mmol) in THF (10 mL) and
3 eq. of Bu4NF (4.74 mL, 1 M in THF, 4.74 mmol) were used. The
reaction was refluxed for 12 h. Flash chromatography (petroleum
ether/EtOAc 70/30) afforded compound 35 as a yellow solid
(161 mg, 76%). Rf: 0.25 (petroleum ether/EtOAc 70/30); mp 211 ꢁC;
Diamond, cmꢀ1
1046, 834, 774;1H NMR (DMSO-d6, 250 MHz)
)
n
2950, 1716, 1593, 1493; 1396, 1301, 1226, 1149,
3.32 (s, 3H,
d
IR (ATR Diamond, cmꢀ1
1148, 1107, 1039, 1011, 830, 776, 734;1H NMR (CDCl3, 400 MHz)
)
n
3403, 2234, 1542, 1451, 1307, 1239, 1222,
SO2CH3), 6.70 (dd, 1H, J ¼ 10 Hz, J’ ¼ 2.5 Hz, H6), 6.88 (s, 1H, H3),
7.02 (s, 1H, H4), 7.25 (d, 1H, J ¼ 10.0 Hz, H7), 8.09 (d, 2H, J ¼ 7.5 Hz,
2 ꢂ H300), 8.14 (d, 2H, J ¼ 7.5 Hz, 2 ꢂ H200), 8.56 (d, 1H, J ¼ 2.0 Hz,
H40), 8.77 (s, 1H, H20), 8.87 (s, 1H, H60), 9.12 (s, 1H, OH), 11.47 (s, 1H,
d
5.13 (s, 2H, OCH2), 7.05 (dd, 1H, J ¼ 5.5 Hz, J’ ¼ 1.5 Hz, H6), 7.15 (d,
1H, J ¼ 1.0 Hz, H3), 7.20 (d, 1H, J ¼ 1.5 Hz, H4), 7.33e7.50 (m, 6H,
H7 þ Harom), 7.85 (d, 2H, J ¼ 5.0 Hz, 2 ꢂ H300), 8.22 (d, 2H,
J ¼ 5.0 Hz, 2 ꢂ H200), 8.86 (s, 1H, H30), 9.05 (s, 1H, H50), 9.29 (s, 1H,
NH);13C NMR (DMSO-d6, 100.6 MHz)
d
43.4 (CH3), 99.7 (CH), 103.8
(CH), 111.8 (CH), 112.9 (CH), 127.6 (2 ꢂ CH), 127.9 (2 ꢂ CH), 129.1

5430
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
(2 ꢂ Cq),129.9 (CH),132.0 (Cq),134.2 (Cq),140.4 (2 ꢂ Cq),141.8 (Cq),
145.9 (2 ꢂ CH), 151.1 (Cq); HRMS (EI-MS): m/z calculated for
C20H17 N2O3S 365.0960 found 365.0966.
7.1.44. 1-Benzenesulfonyl-5-benzyloxy-2-(4-chloro-pyridin-2-yl)-
1H-indole (42)
Compound 6 was obtained following the general procedure A.
A
solution of compound 24 (1.5 g, 2.29 mmol), 2,4-
7.1.41. 2-[6-(4-hydroxy-phenyl)-pyrazin-2-yl]-1H-indol-5-ol (39)
Compound 39 was obtained following the general procedure C.
A solution of compound 34 (200 mg, 0.49 mmol) in CH2Cl2 (10 mL)
and 11.8 eq. of BBr3 (5.8 mL, 5.8 mmol, 1 M in CH2Cl2) were used.
The reaction mixture was stirred for 15 h. After flash chromatog-
raphy (CH2Cl2), compound 39 was obtained as a brown solid
(148 mg, 99%). Rf: 0.25 (CH2Cl2); Mp 195 ꢁC; IR (ATR Diamond,
dichloropyridine (0.37 mL, 3.43 mmol) and CuI (43.8 mg,
0.23 mmol) in THF (32 mL) were used. The reaction was carried
out under
m
Wave irradiation for 30 min at 100 ꢁC. After flash
chromatography (petroleum ether/EtOAc 70/30), compound 42
was obtained as yellow solid (789 g, 72%). Rf: 0.35 (petroleum
ether/EtOAc 60/40); mp 165 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
3068,
3023, 1582, 1543, 1454, 1361, 1262, 1205, 1176, 1147, 1077, 1009,
877, 860, 809, 746, 724, 700.1H NMR (CDCl3, 250 MHz)
5.05 (s,
cmꢀ1
1375, 1227, 1171, 1043, 835, 775;1H NMR (DMSO-d6, 250 MHz)
)
n
3391, 3235, 2958, 2925, 2843, 1719, 1610, 1544, 1512, 1444,
d
2H, OCH2), 6.84 (s, 1H, H3), 6.98 (d, 1H, J ¼ 2.3 Hz, H4), 7.06 (dd,
1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.29e7.45 (m, 9H, Harom þ H50),
7.59 (d, 2H, J ¼ 7.2 Hz, Harom), 7.72 (s, 1H, H30), 8.09 (d, 1H,
J ¼ 9.0 Hz, H7), 8.57 (d, 1H, J ¼ 5.5 Hz, H60);13C NMR(CDCl3,
d
6.73 (dd, 1H, J ¼ 5.5 Hz, J’ ¼ 1.5 Hz, H6), 6.90 (d, 1H, J ¼ 1.0 Hz, H3),
6.94 (d, 2H, J ¼ 5.5 Hz, 2 ꢂ H300), 7.16 (d, 1H, J ¼ 0.8 Hz, H4), 7.33 (d,
1H, J ¼ 5.5 Hz, H7), 8.24 (d, 2H, J ¼ 5.5 Hz, 2 ꢂ H200), 8.20 (s, 1H, OH),
8.96 (s, 1H, H30), 9.02 (s, 1H,H50), 9.95 (s, 1H, OH), 11.45 (s, 1H,
100.6 MHz)
d 69.4 (CH2), 104.1 (CH), 114.5 (CH), 115.6 (CH), 116.5
NH);13C NMR (DMSO-d6, 100.6 MHz)
d
101.2 (CH), 104.0 (CH), 112.6
(CH), 122.4 (CH), 125.4 (CH), 125.9 (CH), 126.5 (CH), 127.0 (CH),
127.6 (2 ꢂ CH), 127.7 (2 ꢂ CH), 130.3 (Cq), 132.0 (Cq), 132.6 (CH),
133.7 (CH), 133.8 (CH), 135.5 (Cq), 136.7 (Cq), 142.5 (Cq), 146.3 (Cq),
148.5 (CH), 151.5 (Cq), 155.4 (Cq); HRMS (EI-MS): m/z calculated
for C26H20 N2O3SCl: 475.0883 found 475.0880.
(Cq), 113.9 (CH), 115.6 (2 ꢂ CH), 118.7 (Cq), 126.5 (Cq), 127.5 (Cq),
128.5 (2 ꢂ CH), 129.0 (Cq), 131.8 (Cq), 132.2 (Cq), 134.5 (CH), 150.2
(CH), 151.1 (CH), 159.4 (Cq); HRMS (EI-MS) m/z calculated for
C18H14 N3O2 304.1086 found 304.1091.
7.1.42. 4-[6-(5-Hydroxy-1H-indol-2-yl)-pyrazin-2-yl]-benzonitrile
(40)
7.1.45. 1-Benzenesulfonyl-2-(4-chloro-pyridin-2-yl)-6-methoxy-
1H-indole (43)
Compound 40 was obtained following the general procedure C.
A solution of compound 35 (145 mg, 0.36 mmol) in CH2Cl2
(10 mL) and 10.0 eq. of BBr3 (3.6 mL, 3.6 mmol, 1 M in CH2Cl2)
were used. The reaction mixture was stirred for 12 h. After flash
chromatography (dichloromethane/MeOH 98/02), compound 40
was obtained as a red solid (111 mg, 99%). Rf: 0.25 (dichꢀlo1ro-
Compound 6 was obtained following the general procedure A. A
solution of compound 3 (828 mg, 1.47 mmol), 2,4-dichloropyridine
(0.24 mL, 2.20 mmol) and CuI (28 mg, 0.147 mmol) in THF (15 mL)
were used. The reaction mixture was charged in a microwave vial
equipped with a stirring bar and subjected to irradiation for 30 min
at 100 ꢁC. After flash chromatography (petroleum ether/EtOAc 70/
30), compound 43 was obtained as yellow oil (414 g, 70%). Rf: 0.3
methane/MeOH 98/02); mp 195 ꢁC; IR (ATR Diamond, cm
) n
3358, 2222, 1542, 1518, 1448, 1383, 1227, 1180, 1159, 1107, 1011,
(petroleum ether/EtOAc 60/40); IR (ATR Diamond, cmꢀ1
2923, 2853, 1614, 1586, 1460, 1371, 1277, 1173, 1112, 1090, 1027, 843,
726, 688;1H NMR (CDCl3, 250 MHz)
3.92 (s, 3H, OCH3), 6.84 (s,1H,
) n 2955,
839, 787, 728, 688;1H NMR (DMSO-d6, 250 MHz)
d
6.76 (dd, 1H,
J ¼ 8.8 Hz, J’ ¼ 2.3 Hz, H6), 6.92 (d, 1H, J ¼ 2.0 Hz, H3), 7.25 (d, 1H,
J ¼ 1.0 Hz, H4), 6.34 (d, 2H, J ¼ 8.8 Hz, H7), 8.07 (d, 2H, J ¼ 8.5 Hz,
2 ꢂ H300), 8.62 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H200), 8.83 (s, 1H, OH), 9.20 (s,
1H, H30), 9.23 (s, 1H, H50), 11.60 (s, 1H, NH);13C NMR (DMSO-d6,
d
H3), 6.88 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.5 Hz, H5), 7.30e7.37 (m, 5H,
3 ꢂ Harom þ H50 þ H4), 7.63 (d, 2H, J ¼ 7.2 Hz, 2 ꢂ Harom), 7.70 (d,
1H, J ¼ 1.7 Hz, H30), 7.73 (d,1H, J ¼ 2.3 Hz, H7), 8.55 (d,1H, J ¼ 5.3 Hz,
100.6 MHz)
d
101.9 (CH), 104.0 (CH), 112.3 (Cq), 112.5 (CH), 114.3
H60);13C NMR (CDCl3, 100.6 MHz)
d 55.8 (CH3), 100.7 (CH), 113.8
(CH), 127.6 (2 ꢂ CH), 128.9 (Cq), 132.3 (2 ꢂ Cq), 132.7 (2 ꢂ CH),
133.9 (Cq), 139.2 (CH), 139.9 (Cq), 141.1 (CH), 145.6 (Cq), 148.0 (Cq),
151.2 (Cq); HRMS (EI-MS): m/z calculated for C19H13 N4O
313.1089 found 313.1078.
(CH), 116.5 (CH), 122.0 (CH), 123.0 (CH), 124.0 (Cq), 126.1 (CH), 126.9
(2 ꢂ CH),128.7 (2 ꢂ CH),133.7 (CH),135.7 (Cq),138.6 (Cq),139.7 (Cq),
143.5 (Cq), 149.5 (CH), 152.7 (Cq), 158.8 (Cq); HRMS (EI-MS): m/z
calculated for C20H16 N2O3SCl: 399.0570 found 399.0574.
7.1.43. 2-[6-(4-Methanesulfonyl-phenyl)-pyrazin-2-yl]-1H-indol-
5-ol (41)
7.1.46. 1-Benzenesulfonyl-5-benzyloxy-2-[4-methoxy-phenyl)-
pyridin-2-yl]-1H-indole (44)
Compound 6 was obtained following the general procedure C.
A solution of compound 36 (300 mg, 0.65 mmol) in CH2Cl2
(10 mL) and 6.0 eq. of BBr3 (3.94 mL, 3.94 mmol, 1 M in CH2Cl2)
were used. The reaction mixture was stirred for 7 h. After flash
chromatography (dichloromethane/MeOH 90/10), compound 41
was obtained as a brown solid (110 mg, 41%). Rf: 0.25 (CH2Cl2/
Compound 6 was obtained following the general procedure B. A
solution of compound 42 (1.7 g, 3.57 mmol) and 4-
methoxyphenylboronic acid (797.8 mg, 5.25 mmol) in a mixture
of toluene (9 mL), ethanol (5.7 mL) and aqueous saturated NaHCO3
solution (4.6 mL) was added. The reaction was carried out under
m
Wave irradiation for 30 min at 150 ꢁC. Flash chromatography
MeOH 90/10); mp 248 ꢁC; IR (ATR Diamond, cmꢀ1
1542, 1450, 1380, 1286, 1233, 1185, 1145, 1089, 1011, 956, 840,
802, 772, 729;1H NMR (DMSO-d6, 250 MHz)
3.31 (s, 3H,
)
n
3346, 2929,
(petroleum ether/EtOAc 60/40) yielded compound 44 as a yellow
oil (1.5 g, 77%). Rf: 0.25 (petroleum ether/EtOAc 60/40); IR (ATR
d
Diamond, cmꢀ1
)
n
3068, 2929, 2831, 1603, 1515, 1449, 1367, 1252,
SO2CH3), 6.76 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.3 Hz, H6), 6.93 (d, 1H,
J ¼ 1.8 Hz, H4), 7.25 (d, 1H, J ¼ 1.2 Hz, H3), 7.35 (d, 1H, J ¼ 8.8 Hz,
H7), 8.11 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H300), 8.66 (d, 2H, J ¼ 8.5 Hz,
2 ꢂ H200), 9.21 (s, 1H, H30), 9.22 (s, 1H,H50), 9.80 (s, 1H, OH), 11.60
1202, 1176, 1146, 1090, 1025, 825, 724;1H NMR (CDCl3, 250 MHz)
d
3.86 (s, 3H, OCH3), 5.05 (s, 2H, OCH2), 6.88 (s, 1H, H3), 6.99e7.05
(m, 3H, 2 ꢂ H300 þ H6), 7.28e7.50 (m, 10H, Harom þ H50 þ H4),7.60
(d, 2H, J ¼ 7.2 Hz, Harom), 7.70 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 7.92 (s,
1H, H30), 8.15 (d, 1H, J ¼ 9.0 Hz, H7), 8.67 (d, 1H, J ¼ 5.2 Hz, H60);13C
(s, 1H, NH);13C NMR (DMSO-d6, 100.6 MHz)
d 43.4 (CH3), 101.9
(CH), 104.1 (CH), 112.5 (CH), 114.3 (CH), 127.4 (2 ꢂ CH), 127.7
(2 ꢂ CH), 128.9 (Cq), 132.4 (Cq), 133.9 (Cq), 139.3 (CH), 140.4 (Cq),
141.1 (CH), 141.7 (Cq), 145.6 (Cq), 148.3 (Cq), 151.2 (Cq); HRMS
(EI-MS): m/z calculated for C19H16 N3O3S 366.0912 found
366.0907.
NMR (CDCl3, 100.6 MHz) d 55.3 (CH3), 70.4 (CH2), 104.9 (CH), 114.5
(2 ꢂ CH), 114.9 (CH), 115.9 (CH), 117.5 (CH), 120.4 (CH), 124.0 (CH),
126.9 (CH), 127.5 (2 ꢂ CH), 127.9 (CH), 128.3 (2 ꢂ CH), 128.5
(2 ꢂ CH), 128.6 (2 ꢂ CH), 130.1 (Cq), 131.6 (Cq), 132.0 (CH), 133.0
(Cq), 133.5 (CH), 136.6 (Cq), 136.8 (Cq), 142.2 (Cq), 147.2 (Cq), 149.2

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5431
(CH), 151.3 (Cq), 156.3 (Cq), 160.6 (Cq); HRMS (EI-MS): m/z calcu-
lated for C33H27 N2O4S: 547.1692 found 547.1702.
116.6 (CH), 119.2 (CH), 121.81 (CH), 123.5 (Cq), 128.1 (2 ꢂ CH), 130.5
(Cq), 135.9 (Cq), 137.3 (Cq), 139.1 (Cq), 148.5 (Cq), 149.4 (CH), 160.6
(Cq); HRMS (EI-MS): m/z calculated for C21H19 N2O2: 331.1447
found 331.1446.
7.1.47. 1-Benzenesulfonyl-6-methoxy-2-[4-4-methoxy-phenyl)-
pyridin-2-yl]-1H-indole (45)
Compound 6 was obtained following the general procedure B. A
solution of compound 43 (420 mg, 1.05 mmol) and 4-
methoxyphenylboronic acid (239.3 mg, 1.57 mmol) in a mixture
of toluene (3 mL), ethanol (2 mL) and aqueous saturated NaHCO3
solution (1.65 mL) was added. The reaction was carried out under
7.1.50. 2-[4-(4-Hydroxy-phenyl)-pyridin-2-yl]-1H-indol-5-ol (48)
Compound 48 was obtained following the general procedure
C. A solution of compound 46 (220 mg, 0.54 mmol) in CH2Cl2
(10 mL) and 8.0 eq. of BBr3 (4.3 mL, 4.32 mmol, 1 M in CH2Cl2)
were used. The reaction mixture was stirred for 12 h. After flash
chromatography (petroleum ether/EtOAc 50/50), compound 48
was obtained as a green solid (162 mg, 99%). Rf: 0.25 (ꢀp1etroleum
m
Wave irradiation for 40 min at 150 ꢁC. Flash chromatography
(petroleum ether/EtOAc 70/30) afforded compound 45 as yellow oil
(394 mg, 79%). Rf: 0.25 (petroleum ether/EtOAc 70/30); IR (ATR
ether/EtOAc 50/50); mp 166 ꢁC; IR (ATR Diamond, cm
) n 3411,
Diamond,cmꢀ1
)
n
3407, 2962, 2929, 2839, 1601, 1515, 1462, 1442,
1279, 1249, 1177, 1113, 1089, 1027, 824, 752, 723;1H NMR (CDCl3,
250 MHz) 3.88 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.87 (m, 2H,
3270, 2929, 2831, 1599, 1544, 1517, 1433, 1374, 1270, 1205, 1176,
1143, 1008, 947, 822, 774;1H NMR (DMSO-d6, 250 MHz)
d
6.66
d
(dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.3 Hz, H6), 6.87 (d, 1H, J ¼ 2.3 Hz, H3),
6.93 (d, 2H, J ¼ 8.5 Hz, 2 ꢂ H300), 7.09 (d, 1H, J ¼ 1.5 Hz, H4), 7.26
(d, 1H, J ¼ 8.7 Hz, H7), 7.50 (dd, 1H, J ¼ 5.2 Hz, J ¼ 1.5 Hz, H50),
7.78 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 7.15 (s, 1H, H30), 8.56 (d, 1H,
J ¼ 5.5 Hz, H60), 8.69 (s, 1H, OH), 9.85 (s, 1H, OH), 11.36 (s, 1H,
H3 þ H5), 7.03 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H300), 7.29e7.50 (m, 5H,
Harom þ H50 þ H4),7.61e7.65 (m, 2H, Harom), 7.69 (d, 2H,
J ¼ 8.8 Hz, 2 ꢂ H200), 7.79 (d, 1H, J ¼ 2.0 Hz, H7), 7.88 (d, 1H,
J ¼ 1.0 Hz, H30), 8.66 (d, 1H, J ¼ 5.3 Hz, H60); 13C NMR (CDCl3,
100.6 MHz)
d
55.4 (CH3), 55.8 (CH3), 100.9 (CH), 113.6 (CH), 114.5
NH);13C NMR (DMSO-d6, 100.6 MHz)
d 100.0 (CH), 103.8 (CH),
(2 ꢂ CH), 115.7 (CH), 120.2 (CH), 121.9 (CH), 123.8 (CH), 124.3 (Cq),
126.9 (2 ꢂ CH), 128.4 (2 ꢂ CH), 128.7 (2 ꢂ CH), 130.4 (Cq), 133.6
(CH), 136.9 (Cq), 139.7 (Cq), 140.3 (Cq), 147.3 (Cq), 149.2 (CH), 151.6
(Cq), 158.5 (Cq), 160.6 (Cq); HRMS (EI-MS): m/z calculated for
C27H23 N2O4S: 471.1379 found 471.1386.
112.2 (CH), 113.0 (CH), 115.7 (CH), 115.8 (2 ꢂ CH), 118.3 (CH), 127.5
(Cq), 128.1 (2 ꢂ CH), 128.9 (2 ꢂ CH), 131.7 (Cq), 147.5 (Cq), 149.5
(CH), 150.8 (Cq), 151.0 (Cq), 158.7 (Cq); HRMS (EI-MS): m/z
calculated for C19H15 N2O2: 303.1134 found 303.1139.
7.1.51. 2-[4-(4-Hydroxy-phenyl)-pyridin-2-yl]-1H-indol-6-ol (49)
Compound 6 was obtained following the general procedure C.
A solution of compound 47 (140 mg, 0.42 mmol) in CH2Cl2
(10 mL) and 5.0 eq. of BBr3 (2.1 mL, 2.1 mmol, 1 M dans CH2Cl2)
were used. The reaction mixture was stirred for 5 h. After flash
chromatography (dichloromethane/MeOH 95/05), compound 49
was obtained as a red solid (125 mg, 97%). Rf: 0.32 (dichꢀlo1ro-
7.1.48. 5-Benzyloxy-2-[4-(4-methoxy-phenyl)-pyridin-2-yl]-1H-
indole (46)
Compound 46 was obtained following the general procedure D.
A solution of compound 44 (430 mg, 0.78 mmol) in THF (20 mL)
and 3.0 eq. of Bu4NF (2.36 mL, 1 M in THF, 2.36 mmol) were used.
The reaction was refluxed for 12 h. Flash chromatography (petro-
leum ether/EtOAc 60/40) afforded compound 46 as a yellow solid
(254 mg, 80%). Rf: 0.25 (petroleum ether/EtOAc 60/40); mp 144 ꢁC;
methane/MeOH 98/02); mp 199 ꢁC; IR (ATR Diamond, cm
) n
3403, 3272, 2929, 2831, 1598, 1544, 1516, 1445, 1355, 1222, 1176,
IR (ATR Diamond, cmꢀ1
1252, 1202, 1178, 1150, 1023, 826, 783, 724, 694;1H NMR (CDCl3,
)
n
3411, 3068, 2929, 2831, 1597, 1515, 1446,
1114, 1043, 1002, 812, 725, 679;1H NMR (DMSO-d6, 250 MHz)
d
6.54 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.3 Hz, H5), 6.84 (d, 1H, J ¼ 1.2 Hz,
250 MHz)
d
3.89 (s, 3H, OCH3), 5.13 (s, 2H, OCH2), 6.96e7.01 (m, 2H,
H3), 6.92 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 7.14 (d, 1H, J ¼ 1.0 Hz, H7),
7.23 (d, 1H, J ¼ 8.5 Hz, H4),7.46 (dd, 1H, J ¼ 5.2 Hz, J ¼ 1.5 Hz,
H50), 7.77 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 8.11 (s, 1H, H30), 8.53 (d, 1H,
J ¼ 5.5 Hz, H60), 9.05 (s, 1H, OH), 9.84 (s, 1H, OH), 11.28 (s, 1H,
H3 þ H6), 7.05 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 7.19 (d, 1H, J ¼ 2.3 Hz,
H4), 7.30e7.43 (m, 7H, Harom þ H50 þ H7), 7.66 (d, 2H, J ¼ 8.8 Hz,
2 ꢂ H200), 7.94 (d, 1H, J ¼ 1.0 Hz, H30), 8.56 (d, 1H, J ¼ 5.2 Hz, H60),
9.60 (s, 1H, NH) 13C NMR (CDCl3, 100.6 MHz)
d
55.4 (CH3), 70.8
NH);13C NMR (DMSO-d6, 100.6 MHz)
d 96.6 (CH), 100.9 (CH),
(CH2), 100.2 (CH), 104.0 (CH), 112.1 (CH), 114.5 (CH), 114.6 (2 ꢂ CH),
117.1 (CH), 119.6 (CH), 127.5 (2 ꢂ CH), 127.8 (CH), 128.2 (2 ꢂ CH),
128.5 (2 ꢂ CH), 129.5 (Cq), 130.5 (Cq), 132.0 (Cq), 137.5 (Cq), 137.7
(Cq), 148.6 (Cq), 149.5 (CH), 150.7 (Cq), 153.6 (Cq), 160.6 (Cq); HRMS
(EI-MS): m/z calculated for C27H23 N2O2: 407.1760 found 407.1772.
110.4 (CH), 115.2 (CH), 115.8 (2 ꢂ CH), 117.9 (CH), 121.0 (CH), 121.8
(Cq), 127.5 (Cq), 128.0 (2 ꢂ CH), 135.6 (Cq), 138.4 (Cq), 147.4 (Cq),
149.4 (CH), 151.2 (Cq), 153.9 (Cq), 158.7 (Cq); HRMS (EI-MS): m/z
calculated for C19H15 N2O2: 303.1134 found 303.1145.
7.1.52. [5-(1-Benzenesulfonyl-5-benzyloxy-1H-indol-2-yl)-pyridin-
3-yl]-(4-methoxy-phenyl)-amine (50)
7.1.49. 6-Methoxy-2-[4-(4-methoxy-phenyl)-pyridin-2-yl]-1H-
indole (47)
Compound 6 was obtained following the general procedure E. A
solution of compound 25 (100 mg, 0.19 mmol) and p-anisidine
(35.4 mg, 0.28 mmol) in 1,4-dioxane (8 mL) was used under
microwave irradiation. After flash chromatography (petroleum
ether/EtOAc 50/50), compound 50 was obtained as yellow solid
(93 mg, 87%). Rf: 0.25 (petroleum ether/EtOAc 30/70); mp 90 ꢁC; IR
Compound 47 was obtained following the general procedure D.
A solution of compound 45 (275 mg, 0.58 mmol) in THF (10 mL) and
3.0 eq. of Bu4NF (1.75 mL, 1 M in THF, 1.75 mmol) were used. The
reaction was refluxed for 4 h. Flash chromatography (petroleum
ether/EtOAc 80/20) afforded compound 47 as a yellow solid
(153 mg, 80%). Rf: 0.45 (petroleum ether/EtOAc 70/30); mp 145 ꢁC;
(ATR Diamond, cmꢀ1
1369, 1174, 1118, 1091, 1025, 852, 820, 741, 726, 686;1H NMR (CDCl3,
250 MHz) 3.81 (s, 3H, OCH3), 5.06 (s, 2H, OCH2), 5.71 (s, 1H, NH),
) n 3378, 2161, 2042, 1977, 1605, 1505, 1438,
IR (ATR Diamond, cmꢀ1
1507,1437,1282, 1249,1218,1180,1156,1109, 1022, 959, 812, 788;1H
NMR (CDCl3, 250 MHz) 3.88 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
) n 3407, 3068, 2929, 2835, 1621, 1596, 1519,
d
d
6.51 (s,1H, H3), 6.91 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H300), 6.96 (d,1H, J ¼ 2.5 Hz,
H4), 7.06 (dd, 1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.18 (d, 2H, J ¼ 9.0 Hz,
2 ꢂ H200), 7.27e7.55 (m, 8H, Harom), 7.63e7.71 (m, 3H, Haromþ H40),
8.02 (s,1H, H20), 8.19 (d,1H, J ¼ 9.0 Hz, H7), 8.29 (s,1H, H60); 13C NMR
6.80 (dd, 1H, J ¼ 8.5 Hz, J’ ¼ 2.2 Hz, H5), 6.90 (s, 1H, H3), 7.01 (s, 1H,
H7), 7.04 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H300), 7.31 (dd, 1H, J ¼ 5.2 Hz,
J’ ¼ 1.8 Hz, H50), 7.53 (d, 1H, J ¼ 8.8 Hz, H4), 7.66 (d, 2H, J ¼ 9.0 Hz,
2 ꢂ H200), 7.91 (d, 1H, J ¼ 0.8 Hz, H30), 8.54 (d, 1H, J ¼ 5.3 Hz, H60),
(CDCl3, 100.6 MHz) d 55.6 (CH3), 70.5 (CH2), 104.6 (CH), 114.7 (CH),
9.45 (s, 1H, NH);13C NMR (CDCl3, 100.6 MHz)
d
55.4 (CH3), 55.6
114.8 (CH), 114.9 (CH), 117.6 (2 ꢂ CH), 122.7 (CH), 126.6 (CH), 127.5
(CH3), 94.2 (CH), 100.5 (CH), 110.6 (CH), 112.5 (CH), 114.5 (2 ꢂ CH),
(2 ꢂ CH), 128.0 (CH), 128.4 (CH), 128.5 (CH), 128.6 (2 ꢂ CH), 128.7

5432
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
(CH), 131.4 (Cq), 131.8 (CH), 131.9 (CH), 132.0 (CH), 132.3 (Cq),
132.1(CH), 133.1 (Cq), 133.7 (CH), 134.0 (Cq), 136.2 (Cq), 136.9 (Cq),
137.1 (Cq), 156.0 (Cq), 156.2 (Cq), 156.4 (Cq); HRMS (EI-MS): m/z
calculated for C33H28 N3O4S 562.1801 found 562.1799.
6.94 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 7.12 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H200), 7.16
(s, 1H, H4), 7.29 (d, 1H, J ¼ 9.0 Hz, H7), 7.34e7.48 (m, 5H, Harom),
7.63 (s, 1H, H40), 8.12 (s, 1H, H20), 8.18 (s, 1H, NH), 8.41 (s, 1H, H60),
11.44 (s, 1H, NH);13C NMR (DMSO-d6, 100.6 MHz)
d 55.2 (CH3), 69.6
(CH2), 99.3 (CH), 103.1 (CH), 112.0 (CH), 112.8 (CH), 112.9 (CH), 114.7
(2 ꢂ CH), 115.3 (CH), 120.9 (2 ꢂ CH), 127.5 (2 ꢂ CH), 128.3 (2 ꢂ CH),
128.7 (Cq), 132.5 (Cq), 134.8 (Cq), 135.6 (Cq), 136.2 (CH), 136.6 (CH),
137.6 (2 ꢂ Cq), 141.6 (Cq), 152.6 (Cq), 154.4 (Cq); HRMS (EI-MS): m/z
calculated for C27H24 N3O2 422.1869 found 422.1883.
7.1.53. [6-(1-Benzenesulfonyl-5-benzyloxy-1H-indol-2-yl)-pyrazin-
2-yl]-(4-methoxy-phenyl)-amine (51)
Compound 6 was obtained following the general procedure E. A
solution of compound 26 (400 mg, 0.84 mmol) and p-anisidine
(155.1 mg, 1.26 mmol) in 1,4-dioxane (8 mL) was used under
microwave irradiation. After flash chromatography (petroleum
ether/EtOAc 50/50), compound 51 was obtained as yellow solid
(392 mg, 83%). Rf: 0.25 (petroleum ether/EtOAc50/50); mp 82 ꢁC; IR
7.1.56. [6-(5-Benzyloxy-1H-indol-2-yl)-pyrazin-2-yl]-(4-methoxy-
phenyl)-amine (54)
Compound 54 was obtained following the general procedure D.
A solution of compound 51 (270 mg, 0.48 mmol) in THF (12 mL) and
10.0 eq. of Bu4NF (4.8 mL, 1 M in THF, 4.8 mmol) were used. The
reaction was refluxed for 12 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 54 as a green solid
(200 mg, 99%). Rf: 0.22 (petroleum ether/EtOAc50/50); mp 227 ꢁC;
(ATR Diamond, cmꢀ1
1237, 1199, 1177, 1151, 1093, 1028, 998, 830, 726, 684;1H NMR
(CDCl3, 250 MHz) 3.82 (s, 3H, OCH3), 5.06 (s, 2H, OCH2), 6.15 (s,
) n 3436, 2165, 1617, 1548, 1507, 1452, 1367,
d
1H, NH), 6.78 (s, 1H, H3), 6.92 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H300), 6.99 (d,
1H, J ¼ 2.3 Hz, H4), 7.07 (dd, 1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6),
7.29e7.45 (m, 10H, Harom þ 2 ꢂ H200), 7.64 (d, 2H, J ¼ 9.5 Hz,
Harom), 8.10 (d, 1H, J ¼ 9.5 Hz, H7), 8.11 (s, 1H, H30), 8.21 (s, 1H,
IR (ATR Diamond, cmꢀ1
1450, 1366, 1294, 1226, 1190, 1173, 1151, 1092, 1019, 833, 798, 728,
689;1H NMR (DMSO-d6, 250 MHz)
3.76 (s, 3H, OCH3), 5.11 (s, 2H,
) n 3452, 2238, 2161, 1981, 1617, 1543, 1509,
H50);13C NMR (CDCl3, 100.6 MHz)
d
55.6 (CH3), 70.5 (CH2), 105.0
d
(CH), 114.7 (2 ꢂ CH), 115.3 (CH), 115.9 (CH), 117.3 (CH), 123.6
(2 ꢂ CH), 127.0 (2 ꢂ CH), 127.5 (2 ꢂ CH), 128.0 (CH), 128.6 (2 ꢂ CH),
128.7 (2 ꢂ CH), 131.0 (CH), 131.2 (Cq), 131.9 (Cq), 133.0 (Cq), 133.6
(CH), 135.3 (CH), 136.8 (Cq), 137.2 (Cq), 139.0 (Cq), 144.4 (Cq), 151.8
(Cq), 156.3 (Cq), 156.6 (Cq); HRMS (EI-MS): m/z calculated for
C32H27 N4O4S 563.1753 found 563.1766.
OCH2), 6.90 (dd, 1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 6.97 (d, 2H,
J ¼ 9.0 Hz, 2 ꢂ H300), 7.07 (s, 1H, H3), 7.12 (d, 1H, J ¼ 1.7 Hz, H4),
7.32e7.49 (m, 6H, Harom þ H7), 7.76 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H200),
8.03 (s, 1H, H30), 8.42 (s, 1H, H50), 9.35 (s, 1H, NH), 11.31 (s, 1H,
NH);13C NMR (DMSO-d6, 100.6 MHz)
d 55.1 (CH3), 69.5 (CH2), 101.6
(CH), 103.2 (CH), 112.7 (CH), 113.8 (CH), 114.1 (2 ꢂ CH), 119.9
(2 ꢂ CH),127.5 (3 ꢂ CH),128.3 (3 ꢂ CH),128.4 (Cq), 132.5 (CH), 133.7
(Cq), 135.6 (Cq), 137.6 (Cq), 142.5 (Cq), 145.6 (Cq), 151.6 (Cq), 152.7
(Cq), 154.1 (Cq); HRMS (EI-MS): m/z calculated for C26H23 N4O2
423.1821 found 423.1822.
7.1.54. [6-(1-Benzenesulfonyl-6-methoxy-1H-indol-2-yl)-pyrazin-
2-yl]-(4-methoxy-phenyl)-amine (52)
Compound 6 was obtained following the general procedure E. A
solution of compound 14 (400 mg,1.0 mmol) and 4-methoxyaniline
(184.72 mg, 1.5 mmol) in 1,4-dioxane (8 mL) was used. After flash
chromatography (petroleum ether/EtOAc 50/50), compound 52
was obtained as yellow oil (415 mg, 86%). Rf: 0.25 (petroleum ether/
7.1.57. [6-(5-methoxy-1H-indol-2-yl)-pyrazin-2-yl]-(4-methoxy-
phenyl)-amine (55)
Compound 56 was obtained following the general procedure D. A
solution of compound 52 (385 mg, 0.79 mmol) in THF (15 mL) and
10.0 eq. of Bu4NF (7.49 mL, 1 M in THF, 7.49 mmol) were used. The
reaction was refluxed for 12 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 55 as a green solid (236 mg,
86%). Rf: 0.25 (petroleum ether/EtOAc 50/50); mp 206 ꢁC; IR (ATR
EtOAc 50/50); IR (ATR Diamond, cmꢀ1
)
n
3436, 2230, 2165, 1732,
1617, 1505, 1439, 1377, 1363, 1275, 1231, 1175, 1155, 1094, 1034, 997,
865, 831, 727, 686; 1H NMR (CDCl3, 250 MHz)
3.82 (s, 3H, OCH3),
d
3.91 (s, 3H, OCH3), 6.51 (s, 1H, NH), 6.79 (s, 1H, H3), 6.87e6.92 (m,
3H, 2 ꢂ H300 þ H4), 6.27e7.49 (m, 6H, Harom þ H5), 7.67 (d, 2H,
J ¼ 8.5 Hz, 2 ꢂ H200), 7.74 (d, 1H, J ¼ 2.0 Hz, H7), 8.10 (s, 1H, H20), 8.21
Diamond, cmꢀ1
1360, 1343, 1176, 1151, 1112, 1093, 1027, 998, 813, 728, 689; 1H NMR
(CDCl3, 250 MHz) 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.40 (s,1H,
) n 3455, 2116, 2030, 1981, 1613, 1498, 1448, 1424,
(s, 1H, H60). 13C NMR (CDCl3, 100.6 MHz)
d 55.5 (CH3), 55.8 (CH3),
100.5 (CH), 113.7 (CH), 114.7 (2 ꢂ CH), 115.7 (CH), 121.9 (CH), 123.5
(CH),123.9 (Cq),126.9 (2 ꢂ CH),128.7 (2 ꢂ CH),130.7 (2 ꢂ CH),132.0
(Cq), 133.6 (CH), 135.1 (CH), 136.9 (Cq), 137.4 (Cq), 139.6 (Cq), 151.7
(Cq), 1356.5 (Cq), 158.6 (2 ꢂ Cq). HRMS (EI-MS): m/z calculated for
C26H23 N4O4S 487.1440 found 487.1449.
d
NH), 6.83 (dd,1H, J ¼ 8.5 Hz, J’ ¼ 2.0 Hz, H5), 6.90 (s,1H, H3), 6.99 (d,
2H, J ¼ 9.0 Hz, 2 ꢂ H300), 7.04 (d, 1H, J ¼ 1.2 Hz, H7), 7.35 (d, 2H,
J ¼ 9.0 Hz, 2 ꢂ H200), 7.55 (d,1H, J ¼ 8.8 Hz, H4), 7.92 (s,1H, H20), 8.45
(s, 1H, H60), 9.10 (s, 1H, NH); 13C NMR (CDCl3, 100.6 MHz)
d 55.6
(2 ꢂ CH3), 94.2 (CH),101.8 (CH),111.0 (CH),114.7 (2 ꢂ CH),122.1 (CH),
123.4 (Cq), 124.1 (2 ꢂ CH), 128.5 (CH), 131.0 (CH), 131.8 (Cq), 133.1
(Cq),137.5 (2 ꢂ Cq),152.0 (Cq),156.8 (Cq),157.6 (Cq); HRMS (EI-MS):
m/z calculated for C20H19 N4O2 347.1508 found 347.1496.
7.1.55. [5-(5-Benzyloxy-1H-indol-2-yl)-pyridin-2-yl]-(4-methoxy-
phenyl)-amine (53)
A solution of NaOH (0.23 mL, 2 M in H2O, 0.46 mmol) was added
to a solution of compound 50 (164 mg, 0.29 mmol) in methanol
(5 mL). The reaction was refluxed under stirring for 12 h. After
cooling, the reaction mixture was concentrated under reduced
pressure. After hydrolysis with water (15 mL), the crude product
was extracted with EtOAc (3 ꢂ 15 mL), the combined organic layers
were washed with brine (10 mL) then dried with MgSO4, and
filtered. The solvents were removed under reduced pressure and
the crude material was purified by flash chromatography (petro-
leum ether/EtOAc 50/50), compound 53 was obtained as a white
solid (85 mg, 70%). Rf: 0.5 (dichloromethane/MeOH 90/10); mp
7.1.58. 1-Benzenesulfonyl-6-benzyloxy-2-(6-chloro-pyrazin-2-yl)-
1H-indole (57)
Compound 57 was obtained following the general procedure A.
A solution of compound 56 (1.5 g, 2.29 mmol), 2,6-dichloropyrazine
(409.4 mg, 2.75 mmol) and CuI (43.6 mg, 0.22 mmol) in THF (20 mL)
were used. The reaction was carried out under mWave irradiation
for 30 min at 100 ꢁC. After flash chromatography (petroleum ether/
EtOAc 80/20), compound 57 was obtained as an orange solid
(989 mg, 91%). Rf: 0.25 (petroleum ether/EtOAc 80/20); mp 57 ꢁC;
211 ꢁC; IR (ATR Diamond, cmꢀ1
1580, 1512, 1453, 1360, 1343, 1282, 1227, 1199, 1177, 1142, 1032, 794;
727; 691. 1H NMR (DMSO-d6, 250 MHz)
3.74 (s, 3H, OCH3), 5.09 (s,
2H, OCH2), 6.78 (s, 1H, H3), 6.84 (dd, 1H, J ¼ 8.8 Hz, J’ ¼ 2.3 Hz, H6),
)
n
3448, 3423, 3048, 2165, 1973,
IR (ATR Diamond, cmꢀ1
)
n
3387, 2949, 2909, 2872, 1604, 1506, 1450,
1368, 1234, 1170, 1118, 1086, 1025, 1004, 812, 722, 689; 1H NMR
(CDCl3, 250 MHz) 5.23 (s, 2H, OCH2), 6.94 (s, 1H, H3), 6.99 (dd, 1H,
J ¼ 8.5 Hz, J’ ¼ 2.3 Hz, H5), 7.33 (d, 1H, J ¼ 9.7 Hz, H4), 7.37e7.54 (m,
d
d

P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
5433
10H, Harom), 7.79 (d, 1H, J ¼ 2.3 Hz, H7), 8.55 (s, 1H, H30), 8.84 (s,
J ¼ 2.0 Hz, H4), 7.32e7.49 (m, 6H, Harom þ H7), 7.60 (d, 2H,
J ¼ 8.8 Hz, 2 ꢂ H200), 7.99 (s, 1H, H30), 8.39 (s, 1H, H50), 9.10 (s, 1H,
OH), 9.20 (s, 1H, NH), 11.27 (s, 1H, NH); 13C NMR (DMSO-d6,
1H, H50). 13C NMR (CDCl3, 100.6 MHz)
d 70.5 (CH2), 101.5 (CH), 115.2
(CH), 118.1 (CH), 122.4 (CH), 123.9 (Cq), 127.0 (2 ꢂ CH), 127.5
(2 ꢂ CH), 128.1 (CH), 128.7 (2 ꢂ CH), 128.8 (2 ꢂ CH), 133.8 (CH),
134.9 (Cq), 136.4 (Cq), 136.7 (Cq), 139.9 (Cq), 142.6 (CH), 143.8 (CH),
146.9 (Cq), 147.8 (Cq), 158.0 (Cq); HRMS (EI-MS): m/z calculated for
C25H19ClN3O3S 476.0836 found 476.0851.
100.6 MHz)
d 69.5 (CH2), 105.1 (CH), 105.4 (CH), 108.8 (CH), 109.3
(CH), 115.1 (CH), 115.3 (CH), 116.4 (CH), 126.6 (CH), 127.6 (CH), 127.8
(CH), 128.3 (CH), 129.2 (CH), 129.4 (CH), 130.9 (Cq), 131.4 (Cq), 134.0
(CH), 134.3 (CH), 135.9 (Cq), 136.8 (Cq), 138.8 (Cq), 141.5 (Cq), 151.0
(Cq), 155.7 (Cq), 157.7 (Cq); HRMS (EI-MS): m/z calculated for
C25H21 N4O2 409.1679 found 409.1665.
7.1.59. 4-[6-(1-Benzenesulfonyl-5-benzyloxy-1H-indol-2-yl)-
pyrazin-2-ylamino]-phenol (58)
Compound 58 was obtained following the general procedure E.
A solution of compound 26 (400 mg, 0.84 mmol) and 4-amino-
phenol (137.5 mg, 1.26 mmol) in 1,4-dioxane (8 mL) was used. After
flash chromatography (petroleum ether/EtOAc 50/50), compound
58 was obtained as a green solid (402 mg, 87%). Rf: 0.22 (petroleum
7.1.62. [6-(6-Benzyloxy-1H-indol-2-yl)-pyrazin-2-yl]-(4-
benzyloxy-phenyl)-amine (61)
Compound 61 was obtained following the general procedure D.
A solution of compound 59 (700 mg, 1.09 mmol) in THF (20 mL) and
10.0 eq of Bu4NF (10.9 mL, 1 M in THF, 10.9 mmol) were used. The
reaction was refluxed for 10 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 61 as a brown solid
(408 mg, 75%). Rf: 0.2 (petroleum ether/EtOAc 50/50); mp 204 ꢁC;
ether/EtOAc 50/50); mp 147 ꢁC; IR (ATR Diamond, cmꢀ1
)
n
3329,
2161, 1732, 1617, 1507, 1449, 1372, 1240, 1225, 1178, 1150, 1010, 825,
745, 726, 693; 1H NMR (DMSO-d6, 250 MHz)
5.09 (s, 2H, OCH2),
d
6.38e6.48 (m, 1H, Harom), 6.72 (d, 2H, J ¼ 9.0 Hz, 2 ꢂ H300), 6.98 (s,
1H, H3), 7.07 (dd, 1H, J ¼ 9.2 Hz, J’ ¼ 2.5 Hz, H6), 7.19 (d, 1H,
J ¼ 2.2 Hz, H4), 7.31e7.42 (m, 7H, Harom), 7.49 (d, 2H, J ¼ 9.0 Hz,
2 ꢂ H200), 7.67 (d, 2H, J ¼ 8.5 Hz, Harom), 7.92 (d, 1H, J ¼ 9.2 Hz, H7),
8.06 (s, 1H, H30), 8.17 (s, 1H, H50), 9.12 (s, 1H, OH), 9.34 (s, 1H, NH);
IR (ATR Diamond, cmꢀ1
1435, 1368, 1256, 1231, 1165, 1115, 1024; 815, 722, 691; 1H NMR
(DMSO-d6, 250 MHz) 5.11 (s, 2H, OCH2), 5.16 (s, 2H, OCH2), 6.84
(dd, 1H, 8.8 Hz, J’
) n 3391, 3035; 2913, 2161, 1597, 1539, 1504,
d
J
¼
¼
2.3 Hz, H5), 7.00e7.33 (m, 4H,
H3 þ H4 þ 2 ꢂ H300), 7.36e7.63 (m, 11H, Harom þ H7), 7.76 (d, 2H,
13C NMR (DMSO-d6,100.6 MHz)
d 69.5 (CH2),105.1 (CH),115.0 (CH),
J ¼ 9.0 Hz, 2 ꢂ H200), 8.01 (s, 1H, H30),8.14 (s, 1H, H50), 9.36 (s, 1H,
115.1 (CH), 115.2 (2 ꢂ CH), 115.4 (CH), 116.3 (CH), 120.7 (2 ꢂ CH),
126.5 (2 ꢂ CH), 127.6 (2 ꢂ CH), 127.7 (CH), 128.3 (2 ꢂ CH), 129.2
(2 ꢂ CH), 130.9 (Cq), 131.7 (Cq), 132.9 (CH), 133.6 (CH), 134.2 (CH),
136.0 (Cq), 136.8 (Cq), 138.9 (Cq), 148.1 (Cq), 151.3 (Cq), 152.5 (Cq),
155.7 (Cq); HRMS (EI-MS): m/z calculated for C31H25 N4O4S
549.1597 found 549.1607. (Scheme 4 and 5)
NH), 11.27 (s, 1H, NH); 13C NMR (DMSO-d6, 100.6 MHz)
d 69.4
(2 ꢂ CH2), 95.8 (CH), 101.9 (CH), 110.9 (CH), 115.1 (CH), 119.8 (CH),
121.3 (CH), 122.6 (Cq), 127.4 (2 ꢂ CH), 127.5 (2 ꢂ CH), 127.6 (Cq),
127.7 (2 ꢂ CH), 128.3 (3 ꢂ CH), 128.6 (CH), 128.7 (CH), 131.3 (CH),
131.4 (CH), 131.9 (CH), 134.0 (Cq), 134.1 (Cq), 137.3 (2 ꢂ Cq), 137.4
(Cq), 138.1 (Cq), 153.1 (Cq), 155.5 (Cq); HRMS (EI-MS): m/z calcu-
lated for C32H27 N4O2 499.1594 found 299.1605.
7.1.60. [6-(1-Benzenesulfonyl-6-benzyloxy-1H-indol-2-yl)-pyrazin-
2-yl]-(4-benzyloxy-phenyl)-amine (59)
7.2. Kinase preparations and assays
Compound 59 was obtained following the general procedure BE.
A solution of compound 57 (700 mg, 1.47 mmol), 4-(benzyloxy)-
aniline hydrochloride (519.9 mg, 2.20 mmol) and 3.0 eq. of K2CO3
(609.5 mg, 4.41 mmol) in 1,4-dioxane (10 mL) were used. After flash
chromatography (petroleum ether/EtOAc 50/50), compound 59
was obtained as a brown solid (743 mg, 80%). Rf: 0.22 ꢀ(p1etroleum
Buffer A: 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, 25 mM TriseHCl
pH 7.5, 50
mg heparin/ml. Buffer C: 60 mM b-glycerophosphate,
15 mM p-nitrophenylphosphate, 25 mM Mops (pH 7.2), 5 Mm
EGTA, 15 mM MgCl2, 1 mM DTT, 1 mM sodium vanadate, 1 mM
henylphosphate. Kinase activities were assayed in Buffer A or C, at
ether/EtOAc 50/50); mp 73 ꢁC; IR (ATR Diamond, cm
)
n
3436,
30 ꢁC, at a final ATP concentration of 15
mM. Blank values were
2157,1605,1503,1448,1422,1366, 1270,1228,1174,1153,1116,1090,
subtracted and activities expressed in% of the maximal activity, i.e.
in the absence of inhibitors. Controls were performed with
appropriate dilutions of DMSO. CDK5/p25 (human, recombinant)
was prepared as previously described [36]. Its kinase activity was
assayed in buffer C, with 1 mg histone H1/mL, in the presence of
1001, 828, 726, 685; 1H NMR (CDCl3, 250 MHz)
d
5.08 (s, 2H, OCH2),
5.22 (s, 2H, OCH2), 6.46 (s, 1H, NH), 6.77 (s, 1H, H3), 6.98 (d, 3H,
J ¼ 8.8 Hz, H5 þ 2 ꢂ H300), 6.20 (d, 1H, J ¼ 7.8 Hz, H4), 7.33e7.71(m,
17H, Harom þ 2 ꢂ H200), 7.81 (d, 1H, J ¼ 2.0 Hz, H7), 8.22 (s, 2H,
H30 þ H50); 13C NMR (CDCl3, 100.6 MHz)
d
70.3 (2 ꢂ CH2), 101.6
15
30
m
m
M [
g
-33P] ATP (3000 Ci/mmol; 10 mCi/mL) in a final volume of
(CH), 114.7 (CH), 115.7 (2 ꢂ CH), 115.8 (CH), 121.9 (CH), 123.3
(2 ꢂ CH), 124.0 (Cq), 127.9 (2 ꢂ CH), 127.4 (3 ꢂ CH), 127.5 (3 ꢂ CH),
128.0 (2 ꢂ CH), 128.5 (2 ꢂ CH), 128.6 (Cq), 128.7 (2 ꢂ CH), 128.8
(2 ꢂ CH), 132.0 (Cq), 132.2 (Cq), 132.6 (Cq), 133.5 (Cq), 136.9
(2 ꢂ Cq), 137.1 (Cq), 139.4 (Cq), 155.7 (Cq), 157.5 (Cq); HRMS (EI-
MS): m/z calculated for C38H31 N4O4S 639.2066 found 639.2062.
L. After 30 min incubation at 30 ꢁC, 25
mL aliquots of super-
natant were spotted onto 2.5 ꢂ 3 cm pieces of Whatman P81
phosphocellulose paper, and, 20 s later, the filters were washed five
times (for at least 5 min each time) in a solution of 10 ml phos-
phoric acid/liter of water. The wet filters were counted in the
presence of 1 mL ACS (Amersham) scintillation fluid. GSK-3ab
(porcine brain, native) was assayed, as described for CDK5/p25 but
7.1.61. 4-[6-(5-Benzyloxy-1H-indol-2-yl)-pyrazin-2-ylamino]-
phenol (60)
in Buffer A and using a GSK-3 specific substrate (GS-1:
YRRAAVPPSPSLSRHSSPHQSpEDEEE) (pS stands for phosphorylated
serine). 15 GS-1 was synthesized by Millegen (Labege, France).
DYRK1A (rat, recombinant, expressed in Escherichia coli as a GST
fusion protein) was purified by affinity chromatography on gluta-
thioneeagarose and assayed as described for CDK5/p25 using
myelin basic protein (1 mg/mL) as a substrate.
Compound 60 was obtained following the general procedure D.
A solution of compound 58 (370 mg, 0.67 mmol) in THF (15 mL) and
4.0 eq. of Bu4NF (2.7 mL, 1 M in THF, 2.7 mmol) were used. The
reaction was refluxed for 8 h. Flash chromatography (petroleum
ether/EtOAc 50/50) afforded compound 60 as green solid (102 mg,
37%). Rf: 0.17 (petroleum ether/EtOAc 50/50); mp 250 ꢁC; IR (ATR
Diamond, cmꢀ1
)
n
3452, 3190, 3031, 1609, 1542, 1507, 1447, 1372,
7.3. Cell culture and survival assay
1226, 1194, 1149, 1023, 832, 796, 727, 690; 1H NMR (DMSO-d6,
250 MHz)
d
5.11 (s, 2H, OCH2), 6.79 (d, 2H, J ¼ 8.8 Hz, 2 ꢂ H300), 6.89
Skin diploid fibroblastic cells were provided by BIOPREDIC
International Company (Rennes, France). Caco-2 cells and Huh7
(dd, 1H, J ¼ 9.0 Hz, J’ ¼ 2.5 Hz, H6), 7.04 (s, 1H, H3), 7.19 (d, 1H,

5434
P. Kassis et al. / European Journal of Medicinal Chemistry 46 (2011) 5416e5434
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This work was supported by grants from the Ligue contre le
Cancer (Comités du Grand Ouest) and the Canceropôle Grand
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